Compounds having affinity for the granulocyte-colony stimulating factor receptor (G-CSFR) and associated uses

ABSTRACT

Novel compounds are provided that bind to G-CSFR. The novel compounds have a peptide chain approximately 6 to 40 amino acids in length that binds to G-CSFR. The compounds are useful as probes for affinity screening. In addition, the compounds have demonstrated agonist or antagonist activity for the G-CSFR, and are therefore useful in treatment of diseases including patients who suffer from a low white blood cell titer. Pharmaceutical compositions and methods of use are provided as well.

TECHNICAL FIELD

The present invention relates generally to novel compounds that haveaffinity for the granulocyte-colony stimulating factor receptor(G-CSFR). More particularly, the invention relates to such compoundswhich act as G-CSF mimetics by activating or inactivating the G-CSFR, orby affecting ligand binding to G-CSFR. The invention additionallyrelates to methods of using the novel compounds and pharmaceuticalcompositions containing a compound of the invention as the active agent.The invention has application in the fields of biochemistry andmedicinal chemistry and particularly provides G-CSF mimetics for use inthe treatment of human disease.

BACKGROUND

Granulocyte-colony stimulating factor (G-CSF) is a hematopoietic growthfactor that specifically stimulates proliferation and differentiation ofcells of the neutrophilic lineage.

G-CSF is a cytokine that binds to and activates the granulocyte-colonystimulating factor receptor (G-CSFR). G-CSFR is expressed on the surfaceof mature neutrophils and cells committed to the neutrophilic lineage,with receptor density varying from 190 to more than 1400 sites per cell.The receptor is a member of the cytokine receptor superfamily; itcontains a cytokine receptor-homologous domain responsible for G-CSFbinding, an immunoglobulin-like domain, three fibronectin type IIIdomains, a transmembrane region, and an intracellular domain. Theobserved affinity of G-CSF for its receptor is about 100 pM.

The complete G-CSF protein has become an important therapeutic agent inclinical indications involving depressed neutrophil counts. Suchindications include chemotherapy-induced neutropenia, AIDS and communityacquired pneumonia. Furthermore, G-CSF antagonists may be useful in thetreatment of some diseases caused by an inappropriate or undesirableactivation of G-CSFR.

There remains a need, however, for compounds that bind specifically toG-CSFR, both for studies of the important biological activities mediatedby the receptor and for treatment of diseases, disorders and conditionsthat would benefit from activating or inactivating G-CSFR. The presentinvention provides such compounds, and also provides pharmaceuticalcompositions and methods for using the compounds as therapeutic agents.

SUMMARY OF THE INVENTION

In one embodiment, the invention provides compounds comprising a peptidechain that binds to G-CSFR. In one aspect, the peptide chain isapproximately 10 to 40 amino acids in length and contains a sequence ofamino acids of formula (I)

 CX₁X₂X₃X₄X₅X₆X₇X₈C (SEQ ID NO: 1)  (I)

wherein each amino acid is indicated by standard one-letterabbreviation, and wherein X₁ is A, N, S, F, D, G, L, T, E, V, P, Q, H, Mor K; X₂ is M, G, R, H, D, I, V, A, S, E, N, F, Y, P, C, W or T; X₃ isE, V, W, F, M, A, N, S, L, T, Y, G or P; X₄ is V, I, G, Q, W, M, T, Y,L, P, D, C, E or A; X₅is M, E, W, L, P, N, I, T, V, F, Y, Q, S, R, W, G,H or D; X₆is H, A, W, Y, V, F, Q, M, N, E, S, D, P or G; X₇ is M, F, Y,V, N, L, H, D, S, W, G, Q, C or T; and X₈ is C, Y, R, I, K, W, L, E, M,H, A, T, F, D, P, G or Q.

In another aspect, the peptide chain is approximately 9 to 40 aminoacids in length and contains a sequence of amino acids of formula (II)

X^(I) ₁X^(I) ₂X^(I) ₃SGWVWX^(I) ₄ (SEQ ID NO: 2)  (II)

wherein each amino acid is indicated by the standard one-letterabbreviation, and wherein X^(I) ₁ is S, Q, R, L or Y; X^(I) ₂ is N, S,T, A or D; X^(I) ₃ is E, D or N; and X^(I) ₄ is L V, T, P or H.

In another aspect, the peptide chain is 6 to 40 amino acids in lengthand contains a sequence of amino acids of formula (III)

ERX^(II) ₁X^(II) ₂X^(II) ₃C (SEQ ID NO: 3)  (III)

wherein each amino acid is indicated by standard one-letterabbreviation, and wherein X^(II) ₁ is D, L, S, G, E, A, K or Y; X^(II) ₂is W, Y, F, L or V; and X^(II) ₃ is F, G, M or L.

In still another aspect, the peptide chain is approximately 9 to 40amino acids in length and contains a sequence of amino acids of formula(IV)

X^(III) ₁MVYX^(III) ₂X^(III) ₃PX^(III) ₄W (SEQ ID NO: 4)  (IV)

wherein each amino acid in indicated by standard one-letterabbreviation, and wherein X^(II) ₁ is D or E; X^(III) ₂ is A or T;X^(III) ₃ is Y or V; and X^(III) ₄ is P or Y.

In an additional aspect, the invention provides compounds comprising apeptide chain approximately 12 to 40 amino acids in length and containsa sequence of amino acids of formula (V)

CX^(IV) ₁X^(IV) ₂X^(IV) ₃X^(IV) ₄X^(IV) ₅X^(IV) ₆X^(IV) ₇X^(IV) ₈X^(IV)₉X^(IV) ₁₀C (SEQ ID NO: 5)  (V)

wherein each amino acid is indicated by standard one-letterabbreviation, and wherein X^(IV) ₁ is E, G, P, N, R, T, W, S, L, H, A, Qor Y; X^(IV) ₂ is S, T, E, A, D, G, W, P, L, N, V, Y, R or M; X^(IV) ₃is R, Y, V, Q, E, T, L, P, S, K, M, A or W; X^(IV) ₄ is L, M, G, F, W,R, S, V, P, A, D, C or T; X^(IV) ₅ is V, T, A, R, S, L, W, C, I, E, P,H, F, D or Q; X^(IV) ₆ is E, Y, G, T, Q, M, S, N, A or P; X^(IV) ₇ is C,V, D, G, L, W, E, V, I, S, M or A; X^(IV) ₈ is S, Y, A, W, P, V, L, Q,G, K, F, I, E or D; X^(IV) ₉ is R, W, M, D, H, V, G, A, Q, L, S, E or Y;X^(IV) ₁₀ is M, L, I, S, V, P, W, F, T, Y, R, or Q.

In another aspect the peptide chain is approximately 9 to 40 amino acidsin length and contains a sequence of amino acids of formula (VI)

X^(V) ₁X^(V) ₂X^(V) ₃X^(V) ₄X^(V) ₅X^(V) ₆CX^(V) ₇X^(V) ₈ (SEQ ID NO:6)  (VI)

wherein each amino acid is indicated by standard one-letterabbreviation, and wherein X^(V) ₁ is E, C, Q, V, or Y; X^(V) ₂ is E, A,L, M, S, W, or Q; X^(V) ₃ is K, R or T; X^(V) ₄ is L, A, or V; X^(V) ₅is R, A, M, H, E, V, L, G, D, Q, or S; X^(V) ₆ is E or V; X^(V) ₇ is Aor G; X^(V) ₈ is R H, G or L.

In a further aspect, the peptide chain is approximately 10 to 40 aminoacids in length that binds to G-CSFR and contains a sequence of aminoacids of formula (VII)

X^(VI) ₁X^(VI) ₂X^(VI) ₃X^(VI) ₄X^(VI) ₅EX^(VI) ₆X^(VI) ₇X^(VI) ₈X^(VI)₉ (SEQ ID NO: 7)  (VII)

wherein each amino acid is indicated by standard one-letterabbreviation, and wherein X^(VI) ₅ is A, E or G; X^(VI) ₂ is E, H or D;X^(VI) ₃ is R or G; X^(VI) ₄ is K, Y, M, N, Q, R, D, I, S or E; X^(VI) ₅is A, S or P; X^(VI) ₆ is E, D, T, Q, K or A: X^(VI) ₇ is R, W, K, L, S,A or Q; X^(VI) ₈ is R or E; and X^(VI) ₉ is W, G, or R.

In a final aspect, the invention also provides peptides that, while notnecessarily corresponding to one of the above-defined formulas, bind toG-CSFR.

In some contexts, the compounds of the invention are preferably in theform of a dimer. It is also preferred, in some contexts, that thecompounds of the invention include a peptide wherein the N-terminus ofthe peptide is coupled to a polyethylene glycol molecule. In somecontexts, it is preferred that the compounds of the invention include apeptide wherein the N-terminus of the peptide is acetylated. Inaddition, it is preferred, in some contexts, that the compounds of theinvention include a peptide wherein the C-terminus of the peptide isamidated.

The invention also provides a pharmaceutical composition that comprisesa therapeutically effective amount of a compound of the invention incombination with a pharmaceutically acceptable carrier, as well as amethod for treating a patient who would benefit from a G-CSFR modulator,the method comprising administering to the patient a therapeuticallyeffective amount of a compound of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A, 1B, 1C, 1D, 1E, 1F, 1G, 1H, 1I, 1J and 1K provide thesequences of representative peptide chains contained within thecompounds of the invention.

FIGS. 2, 3, 4, 5, 6, 7, 8, 9A, 9B 10A, 10B and 11 are graphs showing theresults of various assays described in Examples.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions and Overview

It is to be understood that unless otherwise indicated, this inventionis not limited to specific peptide sequences, molecular structures,pharmaceutical compositions, or the like, as such may vary. It is alsoto be understood that the terminology used herein is for the purpose ofdescribing particular embodiments only and is not intended to belimiting.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a novel compound” in a pharmaceutical composition meansthat more than one of the novel compounds can be present in thecomposition, reference to “a pharmaceutically acceptable carrier”includes combinations of such carriers, and the like.

In this specification and in the claims that follow, reference will bemade to a number of terms which shall be defined to have the followingmeanings:

Amino acid residues in peptides are abbreviated as follows:Phenylalanine is Phe or F; Leucine is Leu or L; Isoleucine is lie or I;Methionine is Met or M; Valine is Val or V; Serine is Ser or S; Prolineis Pro or P; Threonine is Thr or T; Alanine is Ala or A; Tyrosine is Tyror Y; Histidine is His or H; Glutamine is Gln or Q; Asparagine is Asn orN; Lysine is Lys or K; Aspartic Acid is Asp or D; Glutamic Acid is Gluor E; Cysteine is Cys or C; Tryptophan is Trp or W; Arginine is Arg orR; and Glycine is Gly or G. In addition, “1-Nal” is used to refer to1-naphthylalanine, the “2-Nal” is used to refer to 2-naphthylalanine.

Stereoisomers (e.g., D-amino acids) of the twenty conventional aminoacids, unnatural amino acids such as α,α-disubstituted amino acids,N-alkyl amino acids, lactic acid, and other unconventional amino acidsmay also be suitable components for compounds of the present invention.Examples of unconventional amino acids include: β-alanine,1-naphthylalanine, 2-naphthylalanine, 3-pyridylalanine,4-hydroxyproline, O-phosphoserine, N-acetylserine, N-formylmethionine,3-methylhistidine, 5-hydroxylysine, nor-leucine, and other similar aminoacids and imino acids (e.g., 4-hydroxyproline).

“Peptide” or “polypeptide” refers to a polymer in which the monomers arealpha amino acids joined together through amide bonds. Peptides are twoor often more amino acid monomers long. One or more of the peptidechains disclosed herein may appear in the compounds of the present. Itis also contemplated that the peptide chains disclosed herein representonly a portion of the overall peptide included in the compound.

The term “dimer” as in a peptide “dimer” refers to a compound in whichtwo peptide chains are linked; generally, although not necessarily, thetwo peptide chains will be identical and are linked through a linkingmoiety covalently bound to the carboxyl terminus of each chain.

The term “agonist” is used herein to refer to a ligand that binds to areceptor and activates the receptor.

The term “antagonist” is used herein to refer to a ligand that binds toa receptor without activating the receptor. Antagonists are eithercompetitive antagonists or noncompetitive antagonists. A “competitiveantagonist” blocks the receptor site that is specific for the agonist. A“noncompetitive antagonist” inactivates or otherwise affects thefunctioning of the receptor by interacting with a site other than theagonist binding site.

The term “modulator” as in a “G-CSFR-modulator” refers to a compoundthat is either an agonist or antagonist of the G-CSFR.

“Pharmaceutically or therapeutically effective dose or amount” refers toa dosage level sufficient to induce a desired biological result. Thatresult can be alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system.Preferably, this dose or amount will be sufficient to either at leastpartially activate or at least partially inactivate G-CSFR and, thus,alleviate the symptoms associated with an undesired neutrophil count invivo.

An “optimal neutrophil count” refers to a quantity of neutrophils in apatient that is determined by a clinician to be optimal for that patientin light of the patient's disease state, condition, etc.

An “undesired neutrophil count” refers to a quantity of neutrophils in apatient that is determined by a clinician to be not optimal for thatpatient in light of the patient's disease state, condition, etc. Thus,an undesired neutrophil count may be depressed, elevated or even equalto the expected neutrophil count so long as the clinician determinesthat the actual count is not optimal for the patient. The compounds ofthe present invention are intended to, inter alia, provide the clinicianwith compounds that, when administered to a patient, bring thatpatient's neutrophil count closer to an optimal neutrophil count.

The term “treat” as in “treat a disease” is intended to include anymeans of treating a disease in a mammal, including (1) preventing thedisease, i.e., avoiding any clinical symptoms of the disease, (2)inhibiting the disease, that is, arresting the development orprogression of clinical symptoms, and/or (3) relieving the disease,i.e., causing regression of clinical symptoms.

“Optional” or “optionally” means that the subsequently describedcircumstance may or may not occur, so that the description includesinstances where the circumstance occurs and instances where it does not.

By “pharmaceutically acceptable carrier” is meant a material which isnot biologically or otherwise undesirable, i.e., the material may beadministered to an individual along with the selected active agentwithout causing any undesirable biological effects or interacting in adeleterious manner with any of the other components of thepharmaceutical composition in which it is contained.

II. The Compounds

A. Compounds of Formula (I):

In a first embodiment, the invention provides compounds comprising apeptide chain that binds to G-CSFR, wherein the compounds comprise apeptide chain approximately 10 to 40 amino acids in length that binds toG-CSFR and contains a sequence of amino acids of formula (I)

CX₁X₂X₃X₄X₅X₆X₇X₈C (SEQ ID NO: 1)  (I)

wherein each amino acid is indicated by standard one-letterabbreviation, and wherein X₁ is A, N, S, F, D, G, L, T, E, V, P, Q, H, Mor K; X₂ is M, G, R, H, D, I, V, A, S, E, N, F, Y, P, C, W or T; X₃ isE, V, W, F, M, A, N, S, L, T, Y, G or P; X₄ is V, I, G, Q, W, M, T, Y,L, P, D, C, E or A; X₅ is M, E, W, L, P, N, I, T, V, F, Y, Q, S, R, W,G, H or D; X₆ is H, A, W, Y, V, F, Q, M, N, E, S, D, P or G; X₇ is M, F,Y, V, N, L, H, D, S, W, G, Q, C or T; and X₈ is C, Y, R, I, K, W, L, E,M, H, A, T, F, D, P, G or Q.

Preferably X₁ is D or P; X₂ is D or P; X₃ is E or W; X₄ is V, I or Y; X₅is M or L; X₆ is W, Y or F; X₇ is M, Y or D; and X₈ is C or M. Examplesof particularly preferred sequences satisfying formula (I) include, butare not limited to, the following:

CAGEVMHMCC (SEQ ID NO: 8);

CNREIEAMCC (SEQ ID NO: 9);

CADEVMHFCC (SEQ ID NO: 10);

CNREIMWMCC (SEQ ID NO: 11);

CSHEVWWYCC (SEQ ID NO: 12);

CSREVLYYCC (SEQ ID NO: 13);

CFIEGPWVCC (SEQ ID NO: 14);

CFVEGNWYCC (SEQ ID NO: 15);

CAAEVMVNCC (SEQ ID NO: 16);

CSDEVIFYCC (SEQ ID NO: 17);

CDREIMWFCC (SEQ ID NO: 18);

CAHEVMWMCC (SEQ ID NO: 19);

CGSEVTFMCC (SEQ ID NO: 20);

CLEEIMWLCC (SEQ ID NO: 21);

CAREVLAMCC (SEQ ID NO: 22);

CSVEVMQMCC (SEQ ID NO: 23);

CTNVQLMHYC (SEQ ID NO: 24);

CDVWQLFDRC (SEQ ID NO: 25);

CSFVQLNSIC (SEQ ID NO: 26);

CDYWQWFDKC (SEQ ID NO: 27);

CESFWVELWC (SEQ ID NO: 28);

CVPWMFYDLC (SEQ ID NO: 29);

CDPWMFYDLC (SEQ ID NO: 30);

CDPWVLFDEC (SEQ ID NO: 31);

CDHWTYFDMC (SEQ ID NO: 32);

CVVWTLYDKC (SEQ ID NO: 33);

CPDWYQSYMC (SEQ ID NO: 34);

CPDWYSYYMC (SEQ ID NO: 35);

CPEWYTDVMC (SEQ ID NO: 36);

CPDWYLDYMC (SEQ ID NO: 37);

CPEWYLDYMC (SEQ ID NO: 38);

CPDWYLPYMC (SEQ ID NO: 39);

CPEWYLPYMC (SEQ ID NO: 40);

CQDWWVELWC (SEQ ID NO: 41);

CPDWYLPWMC (SEQ ID NO: 42);

CACMLRVVHC (SEQ ID NO: 43);

CQRAGYMLAC (SEQ ID NO: 44);

CHANPVWGEC (SEQ ID NO: 45);

CFWSDWGQTC (SEQ ID NO: 46);

CPHWTSYYMC (SEQ ID NO: 47);

CETLCGACFC (SEQ ID NO: 48);

CATTINDTLC (SEQ ID NO: 49);

CLNYPHPVFC (SEQ ID NO: 50);

CMDGEMAVDC (SEQ ID NO: 51);

CNMGWMSWPC (SEQ ID NO: 52)

CETYADWLGC (SEQ ID NO: 53);

CDPWMFFDMC (SEQ ID NO: 54);

CDPWIWYDLC (SEQ ID NO: 55);

CDPWIMYDRC (SEQ ID NO: 56);

CDPWVFFDIC (SEQ ID NO: 57);

CDPWTYYDLC (SEQ ID NO: 58);

CDPWIFYDRC (SEQ ID NO: 59);

CDPWLFYDLC (SEQ ID NO: 60);

CDPWVWYDLC (SEQ ID NO: 61);

CDPWIFFDRC (SEQ ID NO: 62);

CDPWMFFDQC (SEQ ID NO: 63);

CDPWLWYDRC (SEQ ID NO: 64);

CDVWVWYDQC (SEQ ID NO: 65);

CDPWIYYDLC (SEQ ID NO: 66);

CVPWTLFDLC (SEQ ID NO: 67);

CPAWYLEYMC (SEQ ID NO: 68);

CPDWYLEYMC (SEQ ID NO: 69);

CKYWQWFDKC (SEQ ID NO: 70); and

CDHWMWYDKC (SEQ ID NO: 71).

Other preferred formula (I) sequences include, but are not limited tothe following:

GCNREIEAMCCG (SEQ ID NO: 72);

GCPEWYTDVMCG (SEQ ID NO: 73);

NWYCMDGEMAVDCEAT (SEQ ID NO: 74);

WQSCNMGWMSWPCYFV (SEQ ID NO: 75);

HELCETYADWLGCVEW (SEQ ID NO: 76);

PCDPWMFFDMCERW (SEQ ID NO: 77);

LRGCDPWIWYDLCPAV (SEQ ID NO: 78);

GYLCDPWIFYDRCLGF (SEQ ID NO: 79);

RFACDPWVFFDICGYW (SEQ ID NO: 80);

GYWCDPWTYYDLCLTA (SEQ ID NO: 81);

MWTCDPWIFYDRCFLN (SEQ ID NO: 82);

GSSCDPWLFYDLCLLD (SEQ ID NO: 83);

GGGCDPWVWYDLCWCD (SEQ ID NO: 84);

YTSCDPWIFFDRCMSV (SEQ ID NO: 85);

DPYCDPWMFFDQCAYL (SEQ ID NO: 86);

REFCDPWLWYDRCL (SEQ ID NO: 87);

NTGCDVWVWYDQCFAM (SEQ ID NO: 88);

LVFCDPWIYYDLCMDT (SEQ ID NO: 89);

GCSFVQLNSICG (SEQ ID NO: 90);

GCPAWYLEYMCG (SEQ ID NO: 91);

GCPDWYLEYMCG (SEQ ID NO: 92);

GCKYWQWFDKCG (SEQ ID NO: 93); and

GCDHWMWYDKCG (SEQ ID NO: 94).

B. Compounds of Formula (II):

In another aspect, compounds are provided comprising a peptide chainapproximately 9 to 40 amino acids in length that binds to G-CSFR andcontains a sequence of amino acids of formula (II)

X^(I) ₁X^(I) ₂X^(I) ₃SGWVWX^(I) ₄ (SEQ ID NO: 2)  (II)

wherein each amino acid is indicated by the standard one-letterabbreviation, and wherein X^(I) ₁ is S, Q, R, L or Y; X^(I) ₂ is N, S,T, A or D; X^(I) ₃ is E, D or N; and X^(I) ₄ is L V, T, P or H.

Preferably X^(I) ₁ is S or Q; X^(I) ₂ is S; X^(I) ₃ is N; and X^(I) ₄ isV.

Examples of particularly preferred sequences satisfying formula (II)include, but are not limited to, the following:

SNESGWVWL (SEQ ID NO: 95);

QSNSGWVWV (SEQ ID NO: 96);

RTESGWVWT (SEQ ID NO: 97);

RANSGWVWV (SEQ ID NO: 98);

YDNSGWVWH (SEQ ID NO: 99); and

LSDSGWVWVP (SEQ ID NO: 100).

Other preferred formula (II) sequences include, but are not limited to,the following:

EQSNSGWVWVGGGGC (SEQ ID NO: 101);

CEQSNSGWVWV (SEQ ID NO: 102);

EQSNSGWVWVGGGGCKKK (SEQ ID NO: 103);

EQSNSGWVWVGKKKC (SEQ ID NO: 104);

EQSNSGWVWVGKKK (SEQ ID NO: 105);

KKKEQSNSGWVWV (SEQ ID NO: 106);

EQSNSGWVWVGKKKSKKK (SEQ ID NO: 107);

EQSNSGWVWVGGCKKK (SEQ ID NO: 108);

EQSNSGWVWVGGGGGGCKKK (SEQ ID NO: 109);

SNESGWVWLP (SEQ ID NO: 110);

EQSNSGWVWV (SEQ ID NO: 111);

SRTESGWVWT (SEQ ID NO: 112);

QRANSGWVWV (SEQ ID NO: 113);

DYDNSGWVWH (SEQ ID NO: 114);

EQSNSGWVWVGKKKK (SEQ ID NO: 115);

EQSNSGWVWVGGGGSKKK (SEQ ID NO: 116);

EQSNSGWVWVGGGGS (SEQ ID NO: 117);

EQSNSGWVWVGGGGSEQSNSGWVWVGGGGS (SEQ ID NO: 118);

RYQSFELSDSGWVWVPVARH (SEQ ID NO: 119); and

EQSNSGWVWVGGGGCKKKC (SEQ ID NO: 492).

C. Compounds of Formula (III):

In another aspect, the invention provides compounds comprising a peptidechain approximately 6 to 40 amino acids in length that binds to G-CSFRand contains a sequence of amino acids of formula (III)

ERX^(II) ₁X^(II) ₂X^(II) ₃C (SEQ ID NO: 3)  (III)

wherein each amino acid is indicated by standard one-letterabbreviation, and wherein X^(II) ₁ is D, L, S,G, E, A, K or Y; X^(II) ₂is W, Y, F, L or V; and X^(II) ₃ is F, G, M or L.

Preferably, X^(II) ₁ is D or L; X^(II) ₂ is W; and X^(II) ₃ is F.

Examples of particularly preferred sequences satisfying formula (III)include, but are not limited to, the following:

ERDWFC (SEQ ID NO: 120);

ERDWGC (SEQ ID NO: 121);

ERLWFC (SEQ ID NO: 122);

ERSYFC (SEQ ID NO: 123);

ERGWFC (SEQ ID NO: 124);

EREWFC (SEQ ID NO: 125);

ERAWFC (SEQ ID NO: 126);

ERLYFC (SEQ ID NO: 127);

ERYFMC (SEQ ID NO: 128);

ERLFLC (SEQ ID NO: 129);

ERALMC (SEQ ID NO: 130);

ERDVMC (SEQ ID NO: 131); and

ERKWFC (SEQ ID NO: 132).

Particulary preferred compounds are of the formula:

ETWGERDWFC (SEQ ID NO: 133);

ETWGERDWGC (SEQ ID NO: 134);

STAERLWFCG (SEQ ID NO: 135);

YETAERSYFC (SEQ ID NO: 136);

ADNAERGWFC (SEQ ID NO: 137);

QSNSEREWFC (SEQ ID NO: 138);

STSERAWFCG (SEQ ID NO: 139);

ASWSERGWFC (SEQ ID NO: 140);

ELSSEREWFC (SEQ ID NO: 141);

DMQGERGWFC (SEQ ID NO: 142);

SSSERAWFCG (SEQ ID NO: 143);

GNMRERLYFC (SEQ ID NO: 144);

QPNRERYFMC (SEQ ID NO: 145);

SVTRERLFLC (SEQ ID NO: 146);

IPLSERALMCSSWNC (SEQ ID NO: 147);

WARSERDVMCLSYVC (SEQ ID NO: 148);

QSNSEREWFCG (SEQ ID NO: 149);

QSNSEREWFCGGGGS (SEQ ID NO: 150);

NLEEALAQERLWFCRSGNC (SEQ ID NO: 151); and

NLESYEMEERKWFCKMFSC (SEQ ID NO: 152).

D. Compounds of Formula (IV):

In another aspect, compounds are provided comprising a peptide chainapproximately 9 to 40 amino acids in length that binds to G-CSFR andcontains a sequence of amino acids of formula (IV):

X^(III) ₁MVYX^(III) ₂X^(III) ₃PX^(III) ₄W (SEQ ID NO: 4)  (IV)

wherein each amino acid in indicated by standard one-letterabbreviation, and wherein X^(III) ₁ is D or E; X^(III) ₂ is A or T;X^(III) ₃ is Y or V; and X^(III) ₄ is P or Y.

Examples of particularly preferred sequences satisfying formula (IV)include, but are not limited to, the following:

DMVYAYPPW (SEQ ID NO: 153); and

EMVYTVPYW (SEQ ID NO: 154).

Other preferred formula (IV) sequences include, but are not limited to,the following:

DMVYAYPPWS (SEQ ID NO: 155); and

DEMVYTVPYW (SEQ ID NO: 156).

E. Compounds of Formula (V):

In another aspect, compounds are provided comprising a peptide chainapproximately 12 to 40 amino acids in length that binds to G-CSFR andcontains a sequence of amino acids of formula (V):

CX^(IV) ₁X^(IV) ₂X^(IV) ₃X^(IV) ₄X^(IV) ₅X^(IV) ₆X^(IV) ₇X^(IV) ₈X^(IV)₉X^(IV) ₁₀C (SEQ ID NO: 5)  (V)

wherein each amino acid is indicated by standard one-letterabbreviation, and wherein X^(IV) ₁ is E, G, P, N, R, T, W, S, L, H, A, Qor Y; X^(IV) ₂ is S, T, E, A, D, G, W, P, L, N, V, Y, R or M; X^(IV) ₃is R, Y, V, Q, E, T, L, P, S, K, M, A or W; X^(IV) ₄ is L, M, G, F, W,R, S, V, P, A, D, C or T; X^(IV) ₅ is V, T, A, R, S, L, W, C, I, E, P,H, F, D or Q; X^(IV) ₆ is E, Y, G, T, Q, M, S, N, A or P; X^(IV) ₇ is C,V, D, G, L, W, E, V, I, S, M or A; X^(IV) ₈ is S, Y, A, W, P, V, L, Q,G, K, F, I, E or D; X^(IV) ₉ is R, W, M, D, H, V, G, A, Q, L, S, E or Y;X^(IV) ₁₀ is M, L, I, S, V, P, W, F, T, Y, R, or Q.

Preferably X^(IV) ₁ is E; X^(IV) ₂ is S or A; X^(IV) ₃ is R; X^(IV) ₄ isL; X^(IV) ₅ is V or S; X^(IV) ₆ is E; X^(IV) ₇ is C; X^(IV) ₈ is S;X^(IV) ₉ is R; and X^(IV) ₁₀ is L.

Examples of particularly preferred sequences satisfying formula (V)include, but are not limited to, the following:

CESRLVECSRMC (SEQ ID NO: 157);

CETYMTYVYWLC (SEQ ID NO: 158);

CGERLAECARLC (SEQ ID NO: 159);

CESRLRECSMLC (SEQ ID NO: 160);

CEARLSECSRIC (SEQ ID NO: 161);

CPARLLECSRMC (SEQ ID NO: 162);

CESVGVGDWWSC (SEQ ID NO: 163);

CEDRLVEGPWVC (SEQ ID NO: 164);

CNDQFRTCVDVC (SEQ ID NO: 165);

CRGEWWELYHPC (SEQ ID NO: 166);

CEDTRTGWAWSC (SEQ ID NO: 167);

CTWLSSGELVWC (SEQ ID NO: 168);

CWPPVCEVSGIC (SEQ ID NO: 169);

CSLSPIQLQHLC (SEQ ID NO: 170);

CLARLEECSRFC (SEQ ID NO: 171);

CHNSSPMVGVTC (SEQ ID NO: 172);

CHVSPVQIKALC (SEQ ID NO: 173);

CAAPATSWFQYC (SEQ ID NO: 174);

CASKLHECSLRC (SEQ ID NO: 175);

CEPMDSNGIVQC (SEQ ID NO: 176);

CQYASAADEQRC (SEQ ID NO: 177);

CEYWDEPSLSWC (SEQ ID NO: 178);

CERECFQMLERC (SEQ ID NO: 179);

CGMSTDELDEIC (SEQ ID NO: 180);

CYVSPSTGLYSC (SEQ ID NO: 181);

CEARLVECSRLC (SEQ ID NO: 182);

CESRLSECSRMC (SEQ ID NO: 183);

CELKLQECARRC (SEQ ID NO: 184);

CELKLQEAARRC (SEQ ID NO: 185); and

CLERLEECSRFC (SEQ ID NO: 186).

Other preferred formula (V) sequences include but are not limited to,the following:

GGCESRLVECSRMC (SEQ ID NO: 187);

GGCETYMTYVYWLC (SEQ ID NO: 188);

EWLCESVGVGDWWSC (SEQ ID NO: 189);

YHPCEDRLVEGPWVCCRS (SEQ ID NO: 190);

WLLCNDQFRTCVDVCDNV (SEQ ID NO: 191);

IAECRGEWWELYHPCLAA (SEQ ID NO: 192);

TWYCEDTRTGWAWSCLEL (SEQ ID NO: 193);

QLDCTWLSSGELVWCSDW (SEQ ID NO: 194);

QFDCTWLSSGELVWCSDW (SEQ ID NO: 195);

CWPPVCEVSGICS (SEQ ID NO: 196);

CGCSLSPIQLQHLC (SEQ ID NO: 197);

CGCHVSPVQIKALC (SEQ ID NO: 198);

GCHVSPVQIKALC (SEQ ID NO: 199);

GTSCAAPATSWFQYCVLP (SEQ ID NO: 200);

RMDCASKLHECSLRCAYA (SEQ ID NO: 201);

GVVCEPMDSNGIVQCSMR (SEQ ID NO: 202);

IDVCQYASAADEQRCLRI (SEQ ID NO: 203);

NVLCEYWDEPSLSWCLSS (SEQ ID NO: 204);

CQCERECFQMLERC (SEQ ID NO: 205);

FCSCGMSTDELDEICAIW (SEQ ID NO: 206);

EEVCYVSPSTGLYSCYDQ (SEQ ID NO: 207);

LLDICELKLQECARRCN (SEQ ID NO: 208);

GGGLLDICELKLQECARRCN (SEQ ID NO: 209);

GRTGGGLLDICELKLQECARRCN (SEQ ID NO: 210);

LGIEGRTGGGLLDICELKLQECARRCN (SEQ ID NO: 211);

LLDICELKLQEAARRCN (SEQ ID NO: 212); and

KLLDICELKLQEAARRCN (SEQ ID NO: 213).

Particularly preferred formula (V) sequences are selected from the groupconsisting of:

LLDICELKLQECARRCN (SEQ ID NO: 208);

GGGLLDICELKLQECARRCN (SEQ ID NO: 209);

GRTGGGLLDICELKLQECARRCN (SEQ ID NO: 210);

LGIEGRTGGGLLDICELKLQECARRCN (SEQ ID NO: 211);

LLDICELKLQEAARRCN (SEQ ID NO: 212); and

KLLDICELKLQEAARRCN (SEQ ID NO: 213).

F. Compounds of Formula (VI):

In another aspect, compounds are provided comprising a peptide chainapproximately 9 to 40 amino acids in length that binds to G-CSFR andcontains a sequence of amino acids of formula (VI):

X^(V) ₁X^(V) ₂X^(V) ₃X^(V) ₄X^(V) ₅X^(V) ₆CX^(V) ₇X^(V) ₈ (SEQ ID NO:6)  (VI)

wherein each amino acid is indicated by standard one-letterabbreviation, and wherein X^(V) ₁ is E, C, Q, V, or Y; X^(V) ₂ is E, A,L, M, S, W, or Q; X^(V) ₃ is K, R or T; X^(V) ₄ is L, A, or V; X^(V) ₅is R, A, M, H, E, V, L, G, D, Q, or S; X^(V) ₆ is E or V; X^(V) ₇ is Aor G; X^(V) ₈ is R, H, G or L.

Preferably X^(V) ₁ is E; X^(V) ₂ is A or L; X^(V) ₃ is K or R; X^(V) ₄is L; X^(V) ₆ is E; X^(V) ₇ is A; and X^(V) ₈ is R.

Examples of particularly preferred sequences satisfying formula (VI)include, but are not limited to, the following:

EEKLRECAR (SEQ ID NO: 214);

EARLAECAR (SEQ ID NO: 215);

CMKLMECAR (SEQ ID NO: 216);

ELRLRECAH (SEQ ID NO: 217);

EAKLHECAR (SEQ ID NO: 218);

ELKLAECAR (SEQ ID NO: 219);

EARLEECAR (SEQ ID NO: 220);

EAKLRECAR (SEQ ID NO: 221);

ELRLAECAR (SEQ ID NO: 222);

ESRLAECAR (SEQ ID NO: 223);

EAKLVECAR (SEQ ID NO: 224);

ESRLRECAR (SEQ ID NO: 225);

EAKLAECAR (SEQ ID NO: 226);

QWRLEECAR (SEQ ID NO: 227);

QLRLEECAR (SEQ ID NO: 228);

ELRLEECAR (SEQ ID NO: 229);

EAKLLECAR (SEQ ID NO: 230);

EARAGVCAG (SEQ ID NO: 231);

EAKAGVCAG (SEQ ID NO: 232);

VARLEECAR (SEQ ID NO: 233);

ELKLDECAR (SEQ ID NO: 234);

EWRLQECAR (SEQ ID NO: 235);

EAKLSECAR (SEQ ID NO: 236);

EARLSECAR (SEQ ID NO: 237);

ELKLLECAR (SEQ ID NO: 238);

ELRLQECGR (SEQ ID NO: 239);

EQKLAECAR (SEQ ID NO: 240);

ELRLQECAR (SEQ ID NO: 241);

ELKLEECAR (SEQ ID NO: 242);

ESRLEECAR (SEQ ID NO: 243);

EATVQECAR (SEQ ID NO: 244);

ELKLQECAR (SEQ ID NO: 245);

YSRLEECGR (SEQ ID NO: 246);

ELRLRECAL (SEQ ID NO: 247);

EARLLECAR (SEQ ID NO: 248);

ESRLLECAR (SEQ ID NO: 249);

VLKLEECAR (SEQ ID NO: 250);

ESKLAECAR (SEQ ID NO: 251);

ESKLRECAR (SEQ ID NO: 252);

EYKLGECAR (SEQ ID NO: 253);

ESRLQECAR (SEQ ID NO: 254);

QARLAECAR (SEQ ID NO: 255);

ELKKQECAR (SEQ ID NO: 256);

ESRLSECAR (SEQ ID NO: 257);

EARLEECGR (SEQ ID NO: 258);

ESRLAECGR (SEQ ID NO: 259);

EWRLEECAR (SEQ ID NO: 260);

EARLSECGR (SEQ ID NO: 261);

AARLAECAR (SEQ ID NO: 262);

EWKLAECAR (SEQ ID NO: 263);

ESKLEECAR (SEQ ID NO: 264);

DVKLAECAR (SEQ ID NO: 265);

ELQLEECAR (SEQ ID NO: 266); and

EYKLASCAR (SEQ ID NO: 267).

Other preferred formula (VI) sequences include but are not limited to,the following:

RLSICEEKLRECARGC (SEQ ID NO: 268);

PLTTCEARLAECARQL (SEQ ID NO: 269);

LALCMKLMECARRY (SEQ ID NO: 270);

ELVMCELRLRECAHRA (SEQ ID NO: 271);

PLARCEAKLHECARQL (SEQ ID NO: 272);

LLSVCELKLAECARSK (SEQ ID NO: 273);

RLEWCEARLEECARRC (SEQ ID NO: 274);

RLRVVEAKLRECARGR (SEQ ID NO: 275);

CVAHLELRLAECARQI (SEQ ID NO: 276);

HLARCESRLAECARQL (SEQ ID NO: 277);

RLALLEAKLVECARRL (SEQ ID NO: 278);

DLFSLESRLRECARRV (SEQ ID NO: 279);

AVPVLEAKLAECARRF (SEQ ID NO: 280);

YLQQLQWRLEECARGM (SEQ ID NO: 281);

YLELCQLRLEECARQFN (SEQ ID NO: 282);

ELHICELRLEECARGR (SEQ ID NO: 283);

RVARCELRLAECARKS (SEQ ID NO: 284);

YLEVLESRLAECARWK (SEQ ID NO: 285);

EAKLLECARAR (SEQ ID NO: 286);

ELSLCEARAGVCAGSVTK (SEQ ID NO: 287);

ELSLCEAKAGVCAGSVTK (SEQ ID NO: 288);

ALWQCVARLEECARSR (SEQ ID NO: 289);

CLKSCELKLDECARRM (SEQ ID NO: 290);

ALQTCEWRLQECARSR (SEQ ID NO: 291);

YISQCEAKLAECARLY (SEQ ID NO: 292);

ELSSCEAKLSECARRW (SEQ ID NO: 293);

ELSSCEARLSECARRW (SEQ ID NO: 294);

QLLQCELKLLECARQG (SEQ ID NO: 295);

ELLRCEARLAECARGC (SEQ ID NO: 296);

QLRQCELRLQECGRHGN (SEQ ID NO: 297);

PLTSCEQKLAECARRF (SEQ ID NO: 298);

LLGMCELRLQECARAK (SEQ ID NO: 299);

ELSRCELKLEECARGM (SEQ ID NO: 300);

DCRPCESRLEECARRL (SEQ ID NO: 301);

RLSVCEARLEECARQL (SEQ ID NO: 302);

PLKMCEATVQECARLI (SEQ ID NO: 303);

LLLFCEARLSECARHV (SEQ ID NO: 304);

SLSMCEARLAECARLL (SEQ ID NO: 305);

PLFSCELKLQECARRCN (SEQ ID NO: 306);

SLERCYSRLEECGRRI (SEQ ID NO: 307);

PLTSCELRLRECALRSN (SEQ ID NO: 308);

KLAACELKLAECARRW (SEQ ID NO: 309);

KLAACELRLAECARRW (SEQ ID NO: 310);

ALTRCELRLAECARKI (SEQ ID NO: 311);

LLQQCELKLAECARSI (SEQ ID NO: 312);

QLWQCEARLLECARRS (SEQ ID NO: 313);

RLRLCESRLLECARSL (SEQ ID NO: 314);

QLETCVLKLEECARRCN (SEQ ID NO: 315);

ALSQCELRLAECARSVTK (SEQ ID NO: 316);

ELKLAECARRS (SEQ ID NO: 317);

ALSRCESKLAECARRQ (SEQ ID NO: 318);

LMSTCESKLRECARSL (SEQ ID NO: 319);

SLQRCEYKLGECARSL (SEQ ID NO: 320);

RLELLESRLQECARQLN (SEQ ID NO: 321);

QMEWCQARLAECARCCN (SEQ ID NO: 322);

PLFSCELKKQECARRCN (SEQ ID NO: 323);

LLDKCESRLSECARRL (SEQ ID NO: 324);

LLARCEARLEECGRQC (SEQ ID NO: 325);

DLLYCESRLAECGRM (SEQ ID NO: 326);

ALQMCEWRLEECARRL (SEQ ID NO: 327);

LLTMCEARLSECGRRL (SEQ ID NO: 328);

ALWRCESRLAECARRS (SEQ ID NO: 329);

LLATCAARLAECARQL (SEQID NO: 330);

LQTCEWKLAECARSN (SEQ ID NO: 331);

PLRSCESKLEECARQL (SEQ ID NO: 332);

CLRALDVKLAECARHL (SEQ ID NO: 333);

RLKTLELQLEECARRS (SEQ ID NO: 334);

KLRDVELKLAECARRS (SEQ ID NO: 335);

SLQRCEYKLASCARSL (SEQ ID NO: 336);

RLARCELRLAECARKS (SEQ ID NO: 337);

DLWYLESKLEECARRCN (SEQ ID NO: 338);

DLWYLESKLEECARRANG (SEQ ID NO: 339);

DLWYLESKLEECARRCNG (SEQ ID NO: 340);

KQRELELKLAECARRS (SEQ ID NO: 341);

QMQEWCARLAECARCCN (SEQ ID NO: 342); and

LLDICELKLQECARRAN (SEQ ID NO: 343).

A particularly preferred sequence of formula (VI) is:

LLDICELKLQECARRAN (SEQ ID NO: 343).

G. Compounds of Formula (VII):

In another aspect, the invention provides compounds comprising a peptidechain approximately 10 to 40 amino acids in length that binds to G-CSFRand contains a sequence of amino acids of formula (VII):

X^(VI) ₁X^(VI) ₂X^(VI) ₃X^(VI) ₄X^(VI) ₅EX^(VI) ₆X^(VI) ₇X^(VI) ₈X^(VI)₉ (SEQ ID NO: 7)  (VII)

wherein each amino acid is indicated by standard one-letterabbreviation, and wherein X^(VI) ₁ is A, E or G; X^(VI) ₂ is E, H or D;X^(VI) ₃ is R or G; X^(VI) ₄ is K, Y, M, N, Q, R, D, I, S or E; X^(VI) ₅is A, S or P; X^(VI) ₆ is E, D, T, Q, K or A: X^(VI) ₇ is R, W, K, L, S,A or Q; X^(VI) ₈ is R or E; and X^(VI) ₉ is W, G, or R.

Preferably X^(VI) ₁ is A; X^(VI) ₂ is E; X^(VI) ₃ is R; X^(VI) ₅ is A;X^(VI) ₆ is E; X^(VI) ₇ is R; X^(VI) ₈ is R; and X^(VI) ₉ is W.

Examples of particularly preferred sequences satisfying formula (VII)include, but are not limited to, the following:

AERKAEERRW (SEQ ID NO: 344);

AERYAEEREG (SEQ ID NO: 345);

AERMAEERRW (SEQ ID NO: 346);

AERKAEERRR (SEQ ID NO: 347);

AHRNAEERRW (SEQ ID NO: 348);

AERKSEDWRW (SEQ ID NO: 349);

AERKAEEKRR (SEQ ID NO: 350);

AERQAETRRW (SEQ ID NO: 351);

AERNAEERRW (SEQ ID NO: 352);

AERQAEERRW (SEQ ID NO: 353);

AERRAEERRW (SEQ ID NO: 354);

AERDAEQRRW (SEQ ID NO: 355);

AERIAEERRW (SEQ ID NO: 356);

AERSAEERRW (SEQ ID NO: 357);

AERKAEELRW (SEQ ID NO: 358);

AERKAEESRW (SEQ ID NO: 359);

EERKAEERRW (SEQ ID NO: 360);

ADGKAEERRW (SEQ ID NO: 361);

ADGKAEELRW (SEQ ID NO: 362);

ADGMPEERRW (SEQ ID NO: 363);

ADGEAEKRRW (SEQ ID NO: 364);

ADGNAEERRW (SEQ ID NO: 365);

ADGEAEKARW (SEQ ID NO: 366);

AEGEAEKARW (SEQ ID NO: 367);

GERKAEERRW (SEQ ID NO: 368);

AEREAEERRW (SEQ ID NO: 369);

ADGEAEARRW (SEQ ID NO: 370);

ADGRAEEARW (SEQ ID NO: 371);

AEGRAEEARW (SEQ ID NO: 372);

AEREAEKARW (SEQ ID NO: 373);

AERKAEEQRW (SEQ ID NO: 374);

AERDAEKRRW (SEQ ID NO: 375); and

AEREAEKLRW (SEQ ID NO: 376).

Other preferred formula (VI) sequences include but are not limited to,the following:

MLAERKAEERRWFNTHGRE (SEQ ID NO: 377);

MLAERKAEERRWFNTHGREK (SEQ ID NO: 378);

GGGMLAERKAEERRWFNTHGRE (SEQ ID NO: 379);

CMLAERKAEERRWFNTHGRE (SEQ ID NO: 380);

CMLAERKAEERRWFNTHGREK (SEQ ID NO: 381);

MLAERYAEEREGFNMQWRE (SEQ ID NO: 382);

MLAERMAEERRWFRRMG (SEQ ID NO: 383);

IVAERKAEERRRLNTEGHE (SEQ ID NO: 384);

ILAHRNAEERRWFQKHGR (SEQ ID NO: 385);

MLAERKSEDWRWLKTHGRD (SEQ ID NO: 386);

MLAERKAEEKRRLKTQGRE (SEQ ID NO: 387);

ILAERQAETRRWMRNAGSVTK (SEQ ID NO: 388);

MLAERNAEERRWLKRQCG (SEQ ID NO: 389);

MLAERQAEERRWLKMHGGE (SEQ ID NO: 390);

MLAERRAEERRWLKTQGGD (SEQ ID NO: 391);

MLAERQAEERRWLKTQGRD (SEQ ID NO: 392);

MLAERKAEERRWFKTHGRE (SEQ ID NO: 393);

MLAERKAEERRWFNNQGRE (SEQ ID NO: 394);

MPAERDAEQRRWLKTHGRE (SEQ ID NO: 395);

ILAERIAEERRWLKTQGR (SEQ ID NO: 396);

MLAERKAEERRWLQTHGRE (SEQ ID NO: 397);

ILAERSAEERRWLKTQGRE (SEQ ID NO: 398);

LLAERKAEELRWLKTHGRE (SEQ ID NO: 399);

MLAERKAEERRWLQTHGRE (SEQ ID NO: 400);

MLAERNAEERRW (SEQ ID NO: 401);

MFAERKAEESRWLQSQGRE (SEQ ID NO: 402);

MLEERKAEERRWLKTHGR (SEQ ID NO: 403);

MLAERKAEERRWLKMQGRE (SEQ ID NO: 404);

MLAERNAEERRWFYTHGRE (SEQ ID NO: 405);

MLADGKAEERRWLKTHGLD (SEQ ID NO: 406);

MIADGKAEERRWLKTHGRD (SEQ ID NO: 407);

MLADGKAEELRWLKTQGSD (SEQ ID NO: 408);

MLAERNAEERRWLKTHGRD (SEQ ID NO: 409);

MLADGKAEELRWLKTQGRE (SEQ ID NO: 410);

ILADGKAEERRWLKTHGRD (SEQ ID NO: 411);

MLADGMPEERRWLQTHGRD (SEQ ID NO: 412);

MLADGEAEKRRWLNTHGRD (SEQ ID NO: 413);

MLADGNAEERRWLMTHGRD (SEQ ID NO: 414);

MLADGEAEKARWLKTQGRE (SEQ ID NO: 415);

MLAEGEAEKARWLKTQGRE (SEQ ID NO: 416);

MLADGKAEERRWLKTQGRE (SEQ ID NO: 417);

MLAERKAEERRWLSAHVRE (SEQ ID NO: 418);

LLGERKAEERRWYKTHARE (SEQ ID NO: 419);

MLAERKAEERRWLMTHGHD (SEQ ID NO: 420);

MLAERKAEERRWLKSQCLE (SEQ ID NO: 421);

LLAEREAEERRWFKTHGRE (SEQ ID NO: 422);

MLADGEAEARRWFNMHGRE (SEQ ID NO: 423);

MLADGRAEEARWLKTQGSE (SEQ ID NO: 424);

MLAEGRAEEARWLKTQGSE (SEQ ID NO: 425);

MLAEREAEKARWLKTQGRE (SEQ ID NO: 426);

MMAERKAEEQRWFDIHGRD (SEQ ID NO: 427);

LTAERDAEKRRWLLTHGGE (SEQ ID NO: 428);

MLAERQAEERRWLKSQRGE (SEQ ID NO: 429);

LLAERKAEERRWFATHGRD (SEQ ID NO: 430);

MLAEREAEKLRWLKSQERA (SEQ ID NO: 431);

MLAERKAEERRWLKTHGGE (SEQ ID NO: 432);

KGGGMLAERKAEERRWFNTHGRE (SEQ ID NO: 490); and

KSTGGLTAERDAEKRRWLLTHGGE (SEQ ID NO: 491).

H. Other Active Compounds

In another aspect of the invention, there are provided additionalcompounds comprising a peptide chain approximately 5 to 40 amino acidsin length that binds to G-CSFR and contains a sequence of amino acidsselected from the following compounds:

CTWTDLESVY (SEQ ID NO: 433);

HTTNEQFFMC (SEQ ID NO: 434);

DTWLELESRY (SEQ ID NO: 435);

HNSSPMVGVT(SEQ ID NO: 436);

DWQKTIPAYW (SEQ ID NO: 437);

RWGREGLVAALL (SEQ ID NO: 438);

WSGTRVWRCVVT (SEQ ID NO: 439);

MSLLSYLRS (SEQ ID NO: 440);

LDLLAI (SEQ ID NO: 441);

RIYGVK (SEQ ID NO: 442);

MIWHMFMSLLF (SEQ ID NO: 443);

FFWASWMHLLW (SEQ ID NO: 444);

FDDCWREREQFLFQAL (SEQ ID NO: 445);

CGRASECFRLLEM (SEQ ID NO: 446);

RECFQMLER (SEQ ID NO: 447);

CSIRWDFVPGYGLC (SEQ ID NO: 448);

WMQCWDSLSLCYDM (SEQ ID NO: 449);

ALLMCESKLAECARAR (SEQ ID NO: 450);

LAHCKKRKEECAAG (SEQ ID NO: 451);

SIDGVYLRTSRT (SEQ ID NO: 452);

SIDGVYLRTRSRTRY (SEQ ID NO: 453);

VRWLRGSTLRGLRDR (SEQ ID NO: 454);

DRGGGTVGVYWWESY (SEQ ID NO: 455);

VWGTVGTWLEY (SEQ ID NO: 456);

LMWVSAY (SEQ ID NO: 457);

RASDEYGALVRFCTNL (SEQ ID NO: 458);

NYWCDSNWVCEIA (SEQ ID NO: 459);

LAHCLLRLEECAAG (SEQ ID NO: 460);

LALCLARLRECAGG (SEQ ID NO: 461);

CESRLVECSRM (SEQ ID NO: 462);

LLDIAELKLQECARRCN (SEQ ID NO: 463);

KLLDIAELKLQECCARRCN (SEQ ID NO: 464);

CSTGGGLTAERDAEKRRWLLTHGGE (SEQ ID NO: 465)

LTAERDAEKRRWLLTHGGEGG (SEQ ID NO: 466);

LTAERDAEKRRWLLTHGGEGGK (SEQ ID NO: 467);

LTAERDAEKRRWLLTHGGEGGGGG (SEQ ID NO: 468);

LTAERDAEKRRWLLTHGGEGGGGGK (SEQ ID NO: 469);

ESGWVW (SEQ ID NO: 470);

NSGWVW (SEQ ID NO: 471);

SGWVW (SEQ ID NO: 472);

PLGKCEATCREMARYFN (SEQ ID NO: 473);

SLQRCEYKLASVRGLCN (SEQ ID NO: 474)

DLWYLESKLEEAARRCNG (SEQ ID NO: 475);

PYMGTRSRAKLLRQQ (SEQ ID NO: 476);

RNAGERRWFKTQGWY (SEQ ID NO: 477);

MLAERNADDRRWFNTHGRD (SEQ ID NO: 478);

MMADGRLRNSVGLILWCD (SEQ ID NO: 479);

MLADGRLRNVVG (SEQ ID NO: 480);

LLADVRRRNGVGLLRMGRD (SEQ ID NO: 481);

MLADGRLRNFGG (SEQ ID NO: 482);

TYMTYVYWLC (SEQ ID NO: 483);

RFGERWGL (SEQ ID NO: 484);

HWLWWGWNF (SEQ ID NO: 485);

RECFQMLERC (SEQ ID NO: 486);

ILAHRNAKERRWFQKHGR (SEQ ID NO: 487); and

CSTGGGLTAERDAEKRRWLLTHGGEK (SEQ ID NO: 489).

Particularly preferred sequences are selected from the group consistingof:

LLDIAELKLQECARRCN (SEQ ID NO: 463); and

KLLDIAELKLQECCARRCN (SEQ ID NO: 464).

I. Synthesis of the Peptides:

Standard solid phase peptide synthesis techniques are preferred forsynthesis of the peptides of the present invention. Such techniques aredescribed, for example, by Merrifield (1963) J. Am. Chem. Soc. 85:2149.As is well known in the art, solid phase synthesis using the Merrifieldmethod involves successive coupling of α-amino protected amino acids toa growing support-bound peptide chain. After the initial coupling of aprotected amino acid to a resin support (e.g., a polystyrene resin, achloromethylated resin, a hydroxymethyl resin, a benzhydrylamine resin,or the like, depending on the chemistry used), the α-amino protectinggroup is removed by a choice of reagents, depending on the specificprotecting group. Suitable α-amino protecting groups are those known tobe useful in the art of stepwise synthesis of peptides. Included areacyl type protecting groups (e.g., formyl, trifluoroacetyl, acetyl),aromatic urethane type protecting groups (e.g., benzyloxycarbonyl (Cbz)and substituted Cbz), aliphatic urethane protecting groups (e.g.,t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl),alkyl type protecting groups (e.g., benzyl, triphenylmethyl),fluorenylmethyl oxycarbonyl (Fmoc), alloxycarbonyl (Alloc) and Dde. Theside chain protecting groups (typically ethers, esters, trityl, and thelike) remain intact during coupling; however, the side chain protectinggroup must be removable upon completion of the synthesis of the finalpeptide. Preferred side chain protecting groups, as will appreciated bythose skilled in the art, will depend on the particular amino acid thatis being protected as well as the overall chemistry used. After removalof the α-amino protecting group, the remaining protected amino acids arecoupled stepwise in the desired order. Each protected amino acid isgenerally reacted in about a 3-fold excess using an appropriate carboxylgroup activator such as 2-(1H-benzotriazol-1-yl)-1,1,3,3tetramethyluronium hexafluorophosphate (HBTU) ordicyclohexylcarbodiimide (DCC) in solution, for example, in methylenechloride (CH₂Cl₂), N-methyl pyrrolidone, dimethyl formamide (DMF), ormixtures thereof.

Once the synthesis is complete, the compound is cleaved from the solidsupport by treatment with a reagent such as trifluoroacetic acid,preferably in combination with a scavenger such as ethanedithiol,P-mercaptoethanol or thioanisole. The cleavage reagent not only cleavesthe peptide from the resin, but also cleaves all remaining side chainprotecting groups.

These procedures can also be used to synthesize peptides containingamino acids other than the 20 naturally occurring, genetically encodedamino acids. For instance, naphthylalanine can be substituted fortryptophan, with 1-Nal or 2-Nal. Other synthetic amino acids that can besubstituted into the peptides of the present invention include, but arenot limited to, nor-leucine and 3-pyridylalanine.

III. Variation and Modification of the Compounds

A. Dimer Forms (With a Terminal Linking Moiety):

The compounds of the present invention may be in the form of a dimer,i.e., a compound comprised of two similar (but not necessarilyidentical) peptide sequences. Preferably, the dimer compounds of theinvention have the structure of formula (VIII)

wherein R¹, R², n1, n2, n3, n4, x, y and Lk are defined as follows.

R¹ is a peptide chain that binds to G-CSFR and contains a sequence ofamino acids of the present invention. R² is also a peptide chain thatbinds to G-CSFR and contains a sequence of amino acids of the presentinvention. As previously indicated, R¹ and R² can be the same ordifferent. It is preferred, however, that R¹ and R² are the same.

βA is a β-alanine residue and may or may not be present, meaning thatn1, n2, n3 and n4 are independently zero or 1.

Lk is a terminal linking moiety. If the dimer contains only one linkingmoiety, one of x and y is zero and the other is one. Alternatively, ifthe dimer contains two linking moieties, both x and y are one. Thus, xand y are independently zero or one with the proviso that the sum of xand y is either one or two.

The terminal linking moiety Lk can be any moiety recognized by thoseskilled in the art as suitable for joining the peptides of R¹ and R². Lkis preferably although not necessarily selected from the groupconsisting of a disulfide bond, a carbonyl moiety and a C₁₋₁₂ linkingmoiety optionally terminated with one or two —NH— linkages andoptionally substituted at one or more available carbon atoms with alower alkyl substituent. Preferably, the terminal linking moietycomprises —NH—R³—NH— wherein R³ is lower (C₁₋₆) alkylene substitutedwith a functional group such as a carboxyl group or an amino group thatenables coupling to another molecular moiety (e.g., as may be present onthe surface of a solid support), and is optionally substituted with alower alkyl group. Optimally, the linking moiety is a lysine residue orlysine amide, i.e., a lysine residue wherein the carboxyl group has beenconverted to an amide moiety —CONH₂.

B. Disulfide Bonds:

When a pair of cysteine residues is present in a peptide of theinvention, it is preferred that the pair form a disulfide bond linkingthese residues. The disulfide bond may be present within a singlepeptide chain forming an intramolecular disulfide bond. Alternatively,if the compound includes an additional cysteine-containing peptidechain, the disulfide bond may connect the two chains. In addition, wherean additional pair of cysteine residues exists in the compound, morethan one disulfide bond may be present.

Disulfide bond formation may be effected by techniques well known tothose skilled in the art. One such technique involves employing asuitable oxidizing reagent such that a disulfide bond forms from thefree thiols from a pair of cysteine residues. Undesired disulfide bondformation can be minimized, for example, by protecting the thiol groupsof those cysteine residues not intended to form disulfide bonds andoxidizing the peptide before removal of any protecting groups. Preferredcompounds having disulfide bonds include, by way of example, thefollowing:

A particularly preferred compound having disulfide bonds includes

C. N-Terminal Modifications:

(i) Pegylated Compounds

The peptides and compounds of the invention can advantageously bemodified with or covalently coupled to one or more of a variety ofhydrophilic polymers. It has been found that when the peptide compoundsare derivatized with a hydrophilic polymer, their solubility andcirculation half-lives are increased and their immunogenicity is masked.Quite surprisingly, the foregoing can be accomplished with little, ifany, diminishment in binding activity. Nonproteinaceous polymerssuitable for use in accordance with the present invention include, butare not limited to, polyalkylethers as exemplified by polyethyleneglycol and polypropylene glycol, polylactic acid, polyglycolic acid,polyoxyalkenes, polyvinylalcohol, polyvinylpyrrolidone, cellulose andcellulose derivatives, dextran and dextran derivatives, etc. Generally,such hydrophilic polymers have an average molecular weight ranging fromabout 500 to about 100,000 daltons, more preferably from about 2,000 toabout 60,000 daltons and, even more preferably, from about 5,000 toabout 50,000 daltons. In preferred embodiments, such hydrophilicpolymers have average molecular weights of about 5,000 daltons, 10,000daltons 20,000 daltons and 40,000 daltons.

The peptide compounds of the invention can be derivatized with orcoupled to such polymers using any of the methods set forth in Zallipsky(1995) Bioconjugate Chem. 6:150-165; Monfardini et al. (1995)Bioconjugate Chem. 6:62-69; U.S. Pat. No. 4,640,835; U.S. Pat. No.4,496,689; U.S. Pat. No. 4,301,144; U.S. Pat. No. 4,670,417; U.S. Pat.No. 4,791,192; U.S. Pat. No. 4,179,337 or WO 95/34326.

In a preferred embodiment, the N-terminus of a peptide of the inventionis coupled to a polyethylene glycol molecule. It is particularlypreferred that the polymer is selected from the group consisting ofpolyethylene glycol, polypropylene glycol, polylactic acid, polyglycolicacid and derivatives and combinations thereof. Most preferably thepolymer is polyethylene glycol (PEG), in which case the peptide isreferred to as “PEGylated.” PEG is a linear, water-soluble polymer ofethylene oxide repeating units with two terminal hydroxyl groups. PEGsare classified by their molecular weights which typically range fromabout 500 daltons to about 40,000 daltons. In a presently preferredembodiment, the PEGs employed have an average molecular weight of fromabout 500 to about 80,000 daltons. It is particularly preferred that thepolymer has an average molecular weight of between about 5,000 to 40,000daltons.

The PEG coupled to the peptide compounds of the invention can be eitherranched or unbranched. (See, e.g. Monfardini et al. (1995) BioconjugateChem. 6:62-69.) PEG is commercially available from Shearwater Polymers,Inc. (Huntsville, Ala.), Sigma Chemical Co. and other companies.Suitable PEGs include, but are not limited to, monomethoxypolyethyleneglycol (MePEG-OH), monomethoxypolyethylene glycol-succinate (MePEG-S),monomethoxypolyethylene glycol-succinimidyl succinate (MePEG-S-NHS),monomethoxypolyethylene glycol-amine (MePEG-NH₂),monomethoxypolyethylene glycol-tresylate (MePEG-TRES) andmonomethoxypolyethylene glycol-imidazolyl-carbonyl (MePEG-IM).

Briefly, in one exemplary embodiment, the hydrophilic polymer which isemployed, e.g., PEG, is capped at one terminus by an unreactive groupsuch as a methoxy or ethoxy group. Thereafter, the polymer is activatedat the other terminus by reaction with a suitable activating agent, suchas a cyanuric halide (e.g., cyanuric chloride, bromide or fluoride),diimidazole, an anhydride reagent (e.g., a dihalosuccinic anhydride,such as dibromosuccinic anhydride), acyl azide, p-diazoniumbenzyl ether,3-(p-diazoniumphenoxy)-2-hydroxypropylether, or the like. The activatedpolymer is then reacted with a peptide compound of the invention toproduce a polymer-derivatized peptide compound. Alternatively, afunctional group in the peptide compounds of the invention can beactivated for reaction with the polymer, or two groups can be joined ina concerted coupling reaction using known coupling methods. It will bereadily appreciated that the peptide compounds of the invention can bederivatized with PEG using a myriad of other reaction schemes known tothose of skill in the art.

(ii) Acetylated Compounds

In some instances, the N-terminus of the peptide is acetylated.Preferred acetylated compounds include, by way of example, thefollowing:

Ac-ESGWVW-CONH₂ (SEQ ID NO: 470);

Ac-NSGWVW-CONH₂ (SEQ ID NO: 471); and

Ac-SGWVW-CONH₂ (SEQ ID NO: 472).

The peptides and compounds of the invention can be modified with anacetyl moiety (Ac) using standard techniques known to those skilled inthe art. One such technique includes combining the peptide with anacetylating reagent (e.g., acetyl chloride, acetic anhydride) in asuitable solvent to form the acetylated product. To the extent thatother acetylated products are formed during the reaction, the N-terminusderivative can be isolated using conventional separation techniques.

D. C-Terminal Modifications:

The peptides and compounds of the invention can advantageously bemodified to include an amide functionality at the carboxyl terminus ofthe peptide. Thus, it is preferred that the C-terminus of the peptide isamidated.

In preparing peptides wherein the C-terminus carboxyl group is replacedby the amide —C(O)NR³R⁴ where R³ and R⁴ are independently H or lower(C₁₋₆) alkyl, a benzhydrylamine resin is preferably used as the solidsupport for peptide synthesis. Upon completion of the synthesis, ahydrogen fluoride treatment is employed to release the peptide from thesupport, directly resulting in the free peptide amide (i.e., theC-terminus is —C(O)NH₂). Alternatively, use of a chloromethylated resinduring peptide synthesis coupled with reaction with ammonia (to cleavethe side chain protected peptide from the support) yields the freepeptide amide and reaction with an alkylamine or a dialkylamine yields aside chain protected alkylamide or dialkylamide (i.e., the C-terminus is—C(O)NR³R⁴ where R³ and R⁴ are as defined above). Side chain protectinggroups are then removed in the usual fashion by treatment with hydrogenfluoride to give the free amides, alkylamides, or dialkylamides.

E. Other Modifications:

One can also replace the naturally occurring side chains of the 20genetically encoded amino acids (or the stereoisomeric D amino acids)with other side chains, for instance with groups such as alkyl, loweralkyl, cyclic 4-, 5-, 6- or 7-membered alkyl, amide, amide lower alkyl,amide di(lower alkyl), lower alkoxy, hydroxy, carboxy and the lowerester derivatives thereof, and 4-, 5-, 6- or 7-membered heterocyclic. Inparticular, proline analogues in which the ring size of the prolineresidue is changed from 5 members to 4, 6, or 7 members can be employed.

One can also readily modify the peptides herein by phosphorylation orother methods as described in Hruby et al. (1990) Biochem J.268:249-262. Thus, the peptides of the invention also serve asstructural models for non-peptidic compounds with similar biologicalactivity. For example, the peptide backbones may be replaced with abackbone composed of phosphonates, amidates, carbamates, sulfonamides,secondary amines, and N-methylamino acids.

IV. Utility

The compounds of the invention are useful in vitro as unique tools forunderstanding the biological role of G-CSF, including the evaluation ofthe many factors thought to influence, and be influenced by, theproduction of white blood cells. The present compounds are also usefulin the development of other compounds that bind to G-CSFR, because thecompounds provide important structure-activity relationship (SAR)information that facilitates that development.

Moreover, based on the ability to bind to G-CSFR and related receptors,a compound of the invention can be used as a reagent for detecting aG-CSF receptor or related receptor on living cells, fixed cells, inbiological fluids, in tissue homogenates, in purified, naturalbiological materials, etc. For example, by labeling a compound of theinvention, one can identify a cell expressing G-CSFR on its surface. Inaddition, based on it ability to bind a G-CSFR, a compound of theinvention can be used in in situ staining, FACS (fluorescence-activatedcell sorting), Western blotting, ELISA (enzyme-linked immunoadsorptiveassay), etc. In addition, because of its ability to bind to a G-CSFR, acompound of the invention can be used in receptor purification or inpurifying cells expressing G-CSFR on the cell surface (or insidepermeabilized cells).

A compound of the invention can also be utilized as a commercialresearch reagent for various medical research and diagnostic uses. Suchuses include but are not limited to: (1) use as a calibration standardfor quantitating the activities of candidate G-CSFR antagonists oragonists in a variety of functional assays; (2) use as a blockingreagent in random peptide screening, i.e., in searching for new familiesof G-CSFR peptide ligands; (3) use in the co-crystallization withG-CSFR, i.e., a compound of the invention will allow formation ofcrystals bound to G-CSFR, enabling the determination of receptor/peptidestructure x-ray crystallography; (4) use in inhibiting or decreasing theproliferation and growth of G-CSF-dependent cell lines; and (5) otherresearch and diagnostic applications wherein the action of G-CSFR is tobe mimicked, and the like.

A compound of the invention can also be administered to a warm bloodedanimal, including a human, to treat a disease that would benefit fromthe ability of a compound to mimic the effects of G-CSF in vivo. Thus,the present invention encompasses methods for treating a patient whowould benefit from a G-CSFR modulator, comprising administering to thepatient a therapeutically effective amount of a compound of theinvention to activate G-CSFR. For example, a compound of this inventionwill find use in the treatment of diseases such as a depressedneutrophil count. Although attributable to a myriad of causes, adepressed neutrophil count is commonly associated with chemotherapy,AIDS and pneumonia (particularly community-acquired pneumonia). Thus, itis preferred that a compound of the present invention be used to treat adepressed neutrophil count selected from the group consisting ofchemotherapy-induced neutropenia, AIDS-induced neutropenia andcommunity-acquired pneumonia-induced neutropenia.

In addition, the invention encompasses methods for treating a patientwho would benefit from a G-CSFR modulator, comprising administering tothe patient a therapeutically effective amount of a compound of theinvention that antagonizes the action of G-CSF to the G-CSFR in vivo.For example, these receptor antagonists are administered prior to andduring chemotherapy to confer chemoprotection to the neutrophilprogenitor cells by preventing their proliferation in the presence ofcytotoxic drugs. Once chemotherapy administration is suspended, theadministration of the chemoprotective G-CSFR antagonists is alsosuspended thereby allowing the patient's endogenous G-CSF to stimulateproliferation. Alternatively, the neuirophil progenitor cells may be“rescued” by administration of G-CSF or by a G-CSF agonist, e.g., acompound of the present invention having G-CSF agonist activity.

Accordingly, the invention includes pharmaceutical compositionscomprising, as an active ingredient, at least one of the compounds ofthe invention in association with a pharmaceutical carrier or diluent.The composition can be administered by oral, parenteral (intramuscular,intraperitoneal, intravenous (IV) or subcutaneous) injection,transdermal (either passively or using iontophoresis orelectroporation), or transmucosal (nasal, vaginal, rectal, orsublingual) routes of administration, or using bioerodible inserts, andcan be formulated in dosage forms appropriate for each route ofadministration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert pharmaceutically acceptablecarrier such as sucrose, lactose, or starch. Such dosage forms can alsocomprise, as is normal practice, an additional substance other than aninert diluent, e.g., a lubricating agent such as magnesium stearate. Inthe case of capsules, tablets, and pills, the dosage forms may alsocomprise a buffering agent. Tablets and pills can additionally beprepared with enteric coatings.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions and syrups, with theelixirs containing an inert diluent commonly used in the art, such aswater. These compositions can also include one or more adjuvants, suchas a wetting agent, an emulsifying agent, a suspending agent, asweetening agent, a flavoring agent or a perfuming agent.

Preparations for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions, and emulsions. Examples ofnon-aqueous solvents or vehicles are propylene glycol, polyethyleneglycol, vegetable oils, such as olive oil and corn oil, gelatin, andinjectable organic esters such as ethyl oleate. Such dosage forms mayalso contain one or more adjuvants such as a preserving agent, a wettingagent, an emulsifying agent and a dispersing agent. The dosage forms maybe sterilized by, for example, filtration through a bacteria-retainingfilter, by incorporating sterilizing agents into the compositions, byirradiating the compositions, or by heating the compositions. They canalso be manufactured using sterile water, or some other sterileinjectable medium, prior to use.

Compositions for rectal or vaginal administration are preferablysuppositories which may contain, in addition to the active substance, anexcipient such as cocoa butter or a suppository wax. Compositions fornasal or sublingual administration are also prepared with one or morestandard excipients well known in the art.

The dosage of active ingredient in the compositions of this inventionmay be varied; however, it is necessary that the amount of the activeingredient is such that a suitable dosage form is obtained. The selecteddosage depends upon the desired therapeutic effect, the route ofadministration, the duration of the treatment desired, and other factorswell known to those skilled in the art. Generally, dosage levels ofbetween 0.001 to 10 mg/kg of body weight daily are administered tomammals.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof, that theforegoing description as well as the examples which follow are intendedto illustrate and not limit the scope of the invention. Other aspects,advantages and modifications within the scope of the invention will beapparent to those skilled in the art to which the invention pertains.

All patents, patent applications, and publications mentioned herein arehereby incorporated by reference in their entirety.

EXPERIMENTAL

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how toprepare and use the compounds disclosed and claimed herein. Efforts havebeen made to ensure accuracy with respect to numbers (e.g., amounts,temperature, etc.) but some errors and deviations should be accountedfor. Unless indicated otherwise, parts are parts by weight, temperatureis in ° C. and pressure is at or near atmospheric.

Standard peptide synthetic methods were used, and solid phase reactionswere carried out at room temperature. Unless otherwise indicated, allstarting materials and reagents were obtained commercially, e.g., fromAldrich, Sigma and ICN, and used without further purification. Standardcell culture and cell harvesting procedures were used.

Also, in these examples and throughout this specification, theabbreviations employed have their generally accepted meanings, asfollows:

Ac=acetyl

BSA=bovine serum albumin

DMSO=dimethyl sulfoxide

DTT=dithiothreitol

HPLC=high pressure liquid chromatography

MBP=maltose binding protein

PBS=phosphate-buffered saline

SDS PAGE=sodium dodecyl sulfate polyacrylamide gel electrophoresis

TCEP=tris(2-carboxyethyl) phsophine

TFA=trifluoroacetic acid

Tris=tris[hydroxymethyl]aminomethane

EXAMPLES 1-34 G-CSF Competition Binding Assays

The peptides of Table 1 were synthesized using standard techniques andwere subsequently evaluated to identify whether the peptides exhibitedspecific and/or competitive binding.

Specific binding is binding of a ligand to a specific receptor, asopposed to non-specific binding that is mediated by non-specificinteractions. Specific binding may be measured by subtraction of thenon-specific binding (measured in the presence of saturatingconcentrations of unlabeled ligand) from the total binding (measured inthe absence of saturating amounts of ligand). Typically, the unlabeledligand used was a variant of G-CSF in which the cysteine normally foundat position 17 was converted to serine (CS17).

Determination of competitive binding was also carried out for a numberof peptides. Briefly stated, G-CSFR was purified using standardtechniques. The receptor was then immobilized in microtiter plate wellsthat were coated with acid-treated antibody (A b179) specific for a siteon G-CSFR not involved with G-CSF binding. Separately, ¹²⁵I was coupledto the natural ligand G-CSF using techniques well known in the art. Testpeptides were added to receptor-coated wells and allowed to bind toimmobilized receptor for approximately 30 minutes. ¹²⁵ labeled G-CSF wasthen introduced to the wells and incubated overnight at 4°C. Unbound¹²⁵I labeled G-CSF was removed by washing the plate several timesfollowed by measuring the amount of radioactivity that remained in eachwell using conventional techniques. If no reduction in the amount ofbound ¹²⁵I labeled G-CSF was detected, the peptide did not compete forbinding to the receptor. Alternatively, if reduced amounts or no ¹²⁵Ilabeled G-CSF was detected, the peptide did compete. Non-positiveresults for a particular peptide are not dispositive of that peptide'sactivity: the peptide may exhibit binding under conditions differentfrom those tested.

The results of these assays reveal important information about thestructure activity relationship for peptide and peptide mimetics of theinvention to the G-CSF receptor.

TABLE 1 Comp- Ex. Specific etitive No. Sequence Binding? Binding? 1CAGEVMHMCC (SEQ ID NO: 8) Yes Yes 2 CNREIEAMCC (SEQ ID NO: 9) Yes Yes 3CADEVMHFCC (SEQ ID NO: 10) Yes Yes 4 CDVWQLFDRC (SEQ ID NO: 25) Yes Yes5 CSFVQLNSIC (SEQ ID NO: 26) Yes Yes 6 CVPWMFYDLC (SEQ ID NO: 29) Yes No7 CDPWMFYDLC (SEQ ID NO: 30) Yes No 8 CQRAGYMLAC (SEQ ID NO: 44) No No 9CHANPVWGEC (SEQ ID NO: 45) No No 10 CTWTDLESVY (SEQ ID NO: 433) No No 11CFWSDWGQTC (SEQ ID NO: 46) No No 12 CPDWYQSYMC (SEQ ID NO: 34) Yes Yes13 CPHWTSYYMC (SEQ ID NO: 47) Yes Yes 14 CACMLRVVHC (SEQ ID NO: 43) YesYes 15 CETLCGACFC (SEQ ID NO: 44) No No 16 SNESGWVWLP (SEQ ID NO: 110)Yes No 17 EQSNSGWVWV (SEQ ID NO: 111) Yes No 18 SRTESGWVWT (SEQ ID NO:112) Yes No 19 QRANSGWVWV (SEQ ID NO: 113) Yes No 20 DYDNSGWVWH (SEQ IDNO: 114) Yes No 21 ETWGERDWFC (SEQ ID NO: 133) Yes Yes 22 STAERLWFCG(SEQ ID NO: 135) Yes Yes 23 YETAERSYFC (SEQ ID NO: 119) Yes Yes 24ADNAERGWFC (SEQ ID NO: 137) Yes Yes 25 QSNSEREWFC (SEQ ID NO: 138) YesYes 26 STSERAWFCG (SEQ ID NO: 139) Yes Yes 27 ASWSERGWFC (SEQ ID NO:140) Yes Yes 28 ELSSEREWFC (SEQ ID NO: 141) Yes Yes 29 DMQGERGWFC (SEQID NO: 142) Yes Yes 30 DMVYAYPPWS (SEQ ID NO: 155) Yes No 31 DEMVYTVPYW(SEQ ID NO: 156) Yes Yes 32 HTTNEQFFMC (SEQ ID NO: 434) Yes Yes 33DTWLELESRY (SEQ ID NO: 435) Yes No 34 DWQKTIPAYW (SEQ ID NO: 437) YesYes

EXAMPLES 35-73 G-CSF Radioligand Binding Assays

The peptides of Table 2 were synthesized using standard techniques andwere subsequently evaluated to determine their binding affinities toG-CSFR.

Streptavidin-coated scintillation proximity assay (SPA) beads (Amersham)were mixed with biotinylated anti-receptor immobilizing antibody (Ab179)followed by incubation with soluble G-CSFR harvest. Receptor-coated SPAbeads were washed twice in PBS/0.1% BSA and distributed to wells of awhite polystyrene 96-well microtiter plate (Packard). Serial dilutionsof peptide or peptide mimetic were mixed with a constant amount of ¹²⁵Ilabeled G-CSF (10⁵ cpm; 1290 Ci/mmol) in PBS/0.1% BSA, added to wellscontaining receptor-coated SPA beads, and incubated overnight at 4° C.The binding of radiolabeled G-CSF to the receptor-coated SPA bead bringsthe isotope in close proximity to the scintillant, which allows theemitted radiation to stimulate the scintillant to emit light. Anyunbound radiolabeled ligand is not in close enough proximity to thescintillant to allow such energy transfer and hence no signal isgenerated. The amount of ¹²⁵I labeled G-CSF that was bound atequilibrium was measured by counting the plate in a TopCount (Wallac)microtiter plate luminometer. The assay is conducted over a range ofpeptide concentrations and the results are graphed such that the y-axisrepresents the amount of bound ¹²⁵I labeled G-CSF and the x-axisrepresents the concentration of peptide or peptide mimetic. One candetermine the concentration at which the peptide or peptide mimetic willreduce by 50% (IC₅₀) the amount of ¹²⁵I labeled G-CSF bound toimmobilized G-CSFR. The dissociation constant (K_(d)) for the peptideshould be similar to the measured IC₅₀ using the assay conditionsdescribed above.

The peptides along with their corresponding IC₅₀ values are shown inTable 2. lC₅₀ values are indicated symbolically by the symbols “−”, “+”,and “++”. For examples, those peptides which showed IC₅₀ values inexcess of 200 uM are indicated with a “−”. Those peptides which gaveIC₅₀ values of less than or equal to 200 uM are given a “+”, while thosewhich gave IC₅₀ values of 500 nM or less are indicated with a “++”.Those peptides, which gave lC₅₀ values at or near the cutoff point for aparticular symbol, are indicated with a hybrid designator, e.g., “+/−”.The peptides for which IC₅₀ values were not determined are listed as“N.D.”.

The results of these assays reveal important information about thestructure-activity relationship for peptide and peptide mimetics of theinvention to the G-CSF receptor.

TABLE 2 Ex. No. Sequence IC₅₀ 35 NH₂-EQSNSGWVWV-CONH₂ (SEQ ID NO:111) +36 NH₂-STAERLWFCG-CONH₂ (SEQ ID NO:135) − 37

+ 38 NH₂-QSNSEREWFC-CONH₂ (SEQ ID NO:138) − 39

− 40 NH₂-QSNSEREWFCG-CONH₂ (SEQ ID NO:149) − 41

− 42 Ac-ESGWVW-CONH₂ (SEQ ID NO:470) − 43 Ac-NSGWVW-CONH₂ (SEQ IDNO:471) − 44 Ac-SGWVW-CONH₂ (SEQ ID NO:472) − 45NH₂-EQSNSGWVWVGGGGC-CONH₂ (SEQ ID NO:101) + 46

+ 47 CESRLVECSRM (SEQ ID NO:462) +/− 48 LAHCLLRLEECAAG (SEQ ID NO:460)+/− 49 ALLMCESKLAECARAR (SEQ ID NO:450) +/− 50

+ 51 DLWYLESKLEECARRCNG (SEQ ID NO:340) + 52

+ 53 LLDICELKLQECARRCN (SEQ ID NO:208) ++ 54 GGGLLDICELKLQECARRCN (SEQID NO:209) ++ 55 GRTGGGLLDICELKLQECARRCN (SEQ ID NO:210) ++ 56LGIEGRTGGGLLDICELKLQECARRCN (SEQ ID NO:211) ++ 57 LLDICELKLQECARRAN (SEQID NO:343) + 58 LLDICELKLQEAARRCN (SEQ ID NO:212) + 59Biotin-LLDICELKLQECARRAN (SEQ ID NO:343) + 60 Biotin-KLLDICELKLQEAARRCN(SEQ ID NO:213) + 61 LLDIAELKLQECARRCN (SEQ ID NO:463) + 62Biotin-KLLDIAELKLQECARRCN (SEQ ID NO:464) + 63Biotin-KGGGMLAERKAEERRWFNTHGRE (SEQ ID NO:490) + 64

+/− 65

N.D. 66 H₂N-KSTGGLTAERDAEKRRWLLTHGGE-COOH (SEQ ID NO:491) − 67

+ 68

− 69

− 70 YLELCQLRLEECARQFN (SEQ ID NO:282) + 71 CGCHVSPVQIKALC (SEQ IDNO:198) + 72 GCHVSPVQIKALC (SEQ ID NO:199) − 73 HELCETYADWLGCVEW (SEQ IDNO:76) N.D.

EXAMPLES 74-81 Cell Proliferation and Luminescence Assays

The bioactivity of selected peptides of the invention was measured incell-based assays. Murine NFS-60 cells proliferate in the presence ofG-CSF in a dose dependent manner and were used in standard cellproliferation assays that are well known in the art. Murine IL-3dependent Ba/F3 cells were co-transfected with expression vectorsencoding the full length human G-CSFR and a luciferase reporter genecontrolled by the fos promoter. The Ba/F3 G-CSFR reporter cell line isnot only dependent on the presence of G-CSF for proliferation, but alsoproduces luciferase in response to the addition of G-CSF in a dosedependent manner. The parental, untransfected cell line does not respondto G-CSF or produce luciferase, but remains IL-3 dependent.

Reporter cell assays were performed on the above cell line usingpeptides of the invention. The cells were maintained in completeRPMI-164Q media containing 10% fetal calf serum, 2 mM L-glutamine, 1Xantibiotic-antimycotic solution (Life Technologies), and 10% WEHI-3conditioned media (source of murine IL-3). For reporter assays, cellswere starved overnight in medium which lacks WEHI-3 to reduce luciferaseexpression to background levels. The cells were then washed twice inPBS, resuspended in media which lacks WEHI-3 conditioned media, andadded to wells of a 96-well microtiter plate containing dilutions ofpeptide or G-CSF at 5×10⁴ cells/well. Plates were incubated for 2 hoursat 37° C. in a humidified 5% CO₂ incubator and luciferase activity wasmeasured by the addition of luciferin (LucLite—Packard Biosciences) toeach well. The plates were read in a TopCount (Wallac) microtiter plateluminometer.

To measure the ability of selected peptides of the invention to blockG-CSF mediated receptor activation, dilutions of peptide were combinedwith Ba/F3 G-CSFR reporter cells as described above. After a 30-minuteincubation at 37° C., G-CSF was added to each well. The cells wereincubated for 2 hours at 37° C. and the amount of luciferase producedwas measured as described above.

The following seven peptides were tested for bioactivity:

Examples 74, 75, and 76 showed antagonist activity at highconcentrations in cell-based assays using NFS-60 cells. The stability ofExample 74 in cell culture medium was tested by overnight incubation inNFS-60-conditioned medium; no loss of activity was observed, indicatingthat the peptide is stable to degradation under these conditions.

Examples 77, 78, 79, and 80 showed cell proliferation activity whenfused to the carboxy-terminus of the maltose binding protein (MBP). TheMBP fusion protein of Example 78 in particular showed high affinity in abinding competition assay with ¹²⁵I-GCSF (IC₅₀˜10 nM) and activity in aBa/F3 G-CSFR cell proliferation assay (maximal activity at 100 nM).Parental Ba/F3 cells and Ba/F3 cells expressing the human thrombopoietinreceptor did not proliferate in response to this fusion protein. Westernblot analysis of the fusion protein revealed both monomeric and dimericspecies, however the G-CSFR preferentially binds the dimeric molecule.This is true for most of the MBP fusions tested. Presumably the fusionprotein is dimerized through intermolecular disulfide bonds betweencysteine residues present in the peptide sequence. Cleavage of thepeptide from the carboxy terminus of MBP using Factor Xa caused thepeptide to lose its bioactivity while retaining its binding activity.

The Ba/F3 G-CSFR reporter cell line was used to measure the potency of:

LLDICELKLQECARRCN (SEQ ID NO: 208)  Ex. 81

and other possible G-CSF receptor antagonists.

Ligand mediated G-CSF receptor activation in these cells results in theexpression of luciferase, providing a detectable biological signal.Ba/F3 G-CSFR reporter cells responded to the addition of G-CSF in a dosedependent manner (FIG. 2). The addition of increasing concentrations ofpeptide from Example 81 inhibit this G-CSF response, indicating that thepeptide is a G-CSFR antagonist (FIG. 3).

EXAMPLE 82 Characterization of the Dimer Form of AF15846

The peptide AF15846, i.e., LLDICELKLQECARRCN (SEQ ID NO: 208), was understudy as a G-CSF antagonist for chemoprotection againstchemotherapy-induced neutropenia. The peptide monomer contains three Cysresidues with a mass of 2020.4 (average). This peptide is not active asa monomer but must be oxidized, putatively to a dimer form, foractivity.

Monomer vs. Dimer Forms of AF15846:

AF15846 that had been oxidized in 50 mM Tris, pH 8.0 for 48 hours wasdiluted with PBS, then injected onto a Superdex peptide gel filtrationcolumn equilibrated in PBS at 0.75 mL/min. The results of thischromatography indicated that most of the peptide was in dimer form,with small amounts of monomer remaining (not shown). In contrast,AF15846 that had been stored in acid and then diluted with PBS directlyprior to injection onto the peptide column eluted predominantly as amonomer. Some dimerization apparently occurred either during storage orduring the short period the peptide was at neutral pH prior to andduring size exclusion chromatography. Oxidized peptide also eluted muchlater from a cation exchange column run in salt gradients at low pH,consistent with dimer formation (not shown).

Reverse Phase HPLC Assay for Oxidation of AF15846:

AF15846 was oxidized by incubation in 50 mM Tris, pH 8.0, for 16 to 48hours. Reverse phase HPLC methods using a Vydac 25 cm C-18 column and0.1% TFA/acetonitrile buffers were developed to separate the oxidizeddimer from unoxidized monomer, and to separate several differentdimerized peptide structures. While both high pH reverse phase andcation exchange chromatography were also investigated, low pH reversephase separation on a 25 cm column provided the best separation of themany oxidized forms of the peptide (not shown). The dimer species elutefrom the column with earlier retention times than do the monomerspecies. Samples of oxidized AF15846 were re-reduced with DTT to confirmthe elution order. One additional piece of evidence for the formation ofintermolecular dimers comes from the fact that when oxidation wascarried out at low (0.25 mg/mL) concentrations of peptide, the reactionapparently did not go to completion.

Oxidation of AF15846 Under Various Conditions:

AF15846 was incubated for 48 hours in 50 mM Tris, pH 8, 20% DMSO inwater, 20 mM potassium phosphate, pH 3, or 0.1% TFA at room temperature.Aliquots of each sample were taken at various time points. Oxidation ofthe monomer peptide in Tris resulted in the presence of one major plusone minor oxidized species after several hours. In contrast, oxidationof the peptide in 20% DMSO in water resulted in a complex mixture ofoxidized species, even after the 48 hour incubation. Some oxidation ofthe peptide was observed even at acidic pH, although to a much lesserextent than that observed with either Tris or DMSO as the oxidant.

Activity of Oxidized AF15846 Fractions:

Several fractions containing oxidized AF15846 resulting from treatmentunder the conditions described above were collected subjected to testingin two assays: an ¹²⁵I-G-CSF competition binding assay and an ELISAformat competitive G-CSF receptor-binding assay. In both cases fractionscorresponding to the predominant Tris-oxidized species exhibited thehighest activity. The activity of selected fractions in the ¹²⁵I-G-CSFcompetition binding assay is shown in FIG. 4. While speciescorresponding to the monomer peptide were inactive, matrix-assistedlaser desorption/ionization mass spectrometry (MALDI-MS) confirmed thatthe active, Tris-oxidized species was a peptide dimer.

Determination of the Disulfide Structure of the Active Oxidized Form ofAF15846:

It was hypothesized that the active form of AF15846 would contain oneintrachain disulfide per peptide monomer and one interchain peptidedimer. The three possibilities for this type of structure are shownbelow

To determine if one of these structures was present in the active formof AF1 5846, aliquots of Tris-oxidized AF15846 (not HPLC purified) weredigested with trypsin and subjected to reverse phase HPLC. Trypsindigestion was carried out using an immobilized enzyme column fromPerseptive Biosystems. Digestion was carried out in 25 mM Tris, pH 8, 5mM CaCl₂. Fractions were eluted from the column directly into 0.1% TFAto lower the pH and minimize disulfide scrambling. The resulting trypticfragments were separated by reverse phase HPLC and analyzed by MALDImass spectrometry and Edman sequencing. In addition, an aliquot of thedigest was analyzed by electrospray liquid chromatography/massspectrometry (LC/MS). MALDI MS and sequencing of the tryptic peptidesindicated the presence of peptides corresponding to disulfide bondsbetween Cys-5 and Cys-5, as well as between Cys12 and Cys-12. Thisfinding indicated that there were two interchain disulfide bonds betweenpeptide monomers. This result was confirmed by the LC/MS data (FIG. 5),which identified peptides identical to those found by MALDI MS. Thetyptic peptides are labeled, beginning with the first residue, i.e.,Lys, as follows: T1=residues 1-8; T2=residues 9-14; T1,2=residues 1-14;T2,3=residues 9-15; and “+” indicates adisulfide linkage betweenpeptides. However, an additional minor species was evidently present, asa peptide corresponding to a disulfide bond between Cys-5 and Cys-12,which could be either an intrachain or an interchain disulfide, was alsoseen, albeit at a lower level.

To confirm that the active species contained at least two interchaindisulfides, an aliquot of the HPLC-purified, Tris-oxidized AF15846 shownto be active in competition assays was also digested with trypsin. Theprofile of the purified material was compared to that of theunfractionated Tris oxidation product (FIG. 6, same labeling as in FIG.5). The HPLC profile indicates that the purified material is lacking apeptide corresponding to a Cys-5 to Cys-12 disulfide-linked fragment.This indicated that the active species contains two interchain disulfidebonds. However, the oxidation state of the remaining Cys-16 in eachmonomer was not determined.

The oxidized peptide was also reacted with N-ethylmaleimide (NEM) at 37°C. for 1 hour in 100 mM ammonium acetate, pH 4.1 to see if any free Cysresidues remained in the molecule. If this were the case, treatment withthe alkylating reagent would result in a shift of the HPLC retentiontime. Upon incubation with NEM, no such shift was seen (FIG. 7). Incontrast, when the oxidized peptide was incubated with the disulfidespecific reducing agent TCEP, also in ammonium acetate, a shift to alater retention time, consistent with reduced peptide, was found. Thereduced peptide was modified with NEM to produce a peptide that elutedeven later than the reduced form. These data indicate that all six Cysresidues in the AF15846 active dimer are involved in disulfide bonds.Since previous results showed that Cys-5 is linked to Cys-5 and Cys-12is linked to Cys-12, it seems apparent that the remaining two Cysresidues at position 16 of the monomer are also involved in aninterchain disulfide bond.

To obtain further information about the disulfide bond structure inactive AF15846, the peptide was digested with Lys-C in 50 mM Tris pH7.0/30% acetontrile. The profile of this digest is shown in FIG. 8. Fourmajor peaks are seen. The first peak corresponds to a dimer of residues9-17, as indicated by the MALDI MS spectrum of this fraction. See FIGS.9A and 9B. However, it is not possible to tell with this technique ifall four Cys residues are involved in disulfide formation. The last peakcontains a dimer of residues 1-8. The remaining two peaks representintact peptide (22 min) and an artifact peak. This second digest clearlyindicates that the peptide dimerizes into a parallel structure.

This three parallel interchain disulfide structure, indicated below, isdifferent than that originally predicted. Note that the arrows representsites of cleavage by trypsin.

Incubation of the oxidized peptide at 37° C. at higher pH apparentlyresulted disulfide scrambling and/or degradation of the peptide ascontrol peptide fractions incubated at pH 6.0 or pH 7.5 in parallel withNEM-treated fractions exhibited complex HPLC patterns after incubation.It was necessary to drop to pH 4.1 to obtain clean profiles upon NEMtreatment.

A Bioassay for Determining Activity of G-CSF Antagonists:

A biosassay was used to measure the potency of AF15846 and otherpossible G-CSF receptor antagonists. This bioassay utilizes a Ba/F3 cellline containing the rhGCSF receptor and a c-fos promoter/luciferase geneconstruct (Ba/F3/rhGCSF-R/pFos-1cf). Competent binding of a ligand tothe receptor results in expression of lucifierase as the biologicalreadout. Addition of AF15846 to the assay results in the dose-responsecurve shifting to higher concentrations, indicating that the peptide isinhibiting the binding of G-CSF to the expressed receptor (FIGS. 10A and10B). Conversely, the inclusion of various levels of peptide in theassay causes an increase in the amount of G-CSF required to produce asignal, also indicating that the peptide inhibits G-CSF binding (FIG.11).

491 1 10 PRT Artificial Sequence Description of Artificial SequenceFormula peptide sequence 1 Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Cys 1 510 2 9 PRT Artificial Sequence Description of Artificial SequenceFormula peptide sequence 2 Xaa Xaa Xaa Ser Gly Trp Val Trp Xaa 1 5 3 6PRT Artificial Sequence Description of Artificial Sequence Formulapeptide sequence 3 Glu Arg Xaa Xaa Xaa Cys 1 5 4 9 PRT ArtificialSequence Description of Artificial Sequence Formula peptide sequence 4Xaa Met Val Tyr Xaa Xaa Pro Xaa Trp 1 5 5 12 PRT Artificial SequenceDescription of Artificial Sequence Formula peptide sequence 5 Cys XaaXaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Cys 1 5 10 6 9 PRT ArtificialSequence Description of Artificial Sequence Formula peptide sequence 6Xaa Xaa Xaa Xaa Xaa Xaa Cys Xaa Xaa 1 5 7 10 PRT Artificial SequenceDescription of Artificial Sequence Formula peptide sequence 7 Xaa XaaXaa Xaa Xaa Glu Xaa Xaa Xaa Xaa 1 5 10 8 10 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 8 Cys Ala Gly GluVal Met His Met Cys Cys 1 5 10 9 10 PRT Artificial Sequence Descriptionof Artificial Sequence Synthetic peptide 9 Cys Asn Arg Glu Ile Glu AlaMet Cys Cys 1 5 10 10 10 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 10 Cys Ala Asp Glu Val Met His PheCys Cys 1 5 10 11 10 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 11 Cys Asn Arg Glu Ile Met Trp Met Cys Cys 15 10 12 10 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 12 Cys Ser His Glu Val Trp Trp Tyr Cys Cys 1 5 10 1310 PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 13 Cys Ser Arg Glu Val Leu Tyr Tyr Cys Cys 1 5 10 14 10 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide14 Cys Phe Ile Glu Gly Pro Trp Val Cys Cys 1 5 10 15 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 15 Cys PheVal Glu Gly Asn Trp Tyr Cys Cys 1 5 10 16 10 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 16 Cys Ala Ala GluVal Met Val Asn Cys Cys 1 5 10 17 10 PRT Artificial Sequence Descriptionof Artificial Sequence Synthetic peptide 17 Cys Ser Asp Glu Val Ile PheTyr Cys Cys 1 5 10 18 10 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 18 Cys Asp Arg Glu Ile Met Trp PheCys Cys 1 5 10 19 10 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 19 Cys Ala His Glu Val Met Trp Met Cys Cys 15 10 20 10 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 20 Cys Gly Ser Glu Val Thr Phe Met Cys Cys 1 5 10 2110 PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 21 Cys Leu Glu Glu Ile Met Trp Leu Cys Cys 1 5 10 22 10 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide22 Cys Ala Arg Glu Val Leu Ala Met Cys Cys 1 5 10 23 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 23 Cys SerVal Glu Val Met Gln Met Cys Cys 1 5 10 24 10 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 24 Cys Thr Asn ValGln Leu Met His Tyr Cys 1 5 10 25 10 PRT Artificial Sequence Descriptionof Artificial Sequence Synthetic peptide 25 Cys Asp Val Trp Gln Leu PheAsp Arg Cys 1 5 10 26 10 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 26 Cys Ser Phe Val Gln Leu Asn SerIle Cys 1 5 10 27 10 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 27 Cys Asp Tyr Trp Gln Trp Phe Asp Lys Cys 15 10 28 10 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 28 Cys Glu Ser Phe Trp Val Glu Leu Trp Cys 1 5 10 2910 PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 29 Cys Val Pro Trp Met Phe Tyr Asp Leu Cys 1 5 10 30 10 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide30 Cys Asp Pro Trp Met Phe Tyr Asp Leu Cys 1 5 10 31 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 31 Cys AspPro Trp Val Leu Phe Asp Glu Cys 1 5 10 32 10 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 32 Cys Asp His TrpThr Tyr Phe Asp Met Cys 1 5 10 33 10 PRT Artificial Sequence Descriptionof Artificial Sequence Synthetic peptide 33 Cys Val Val Trp Thr Leu TyrAsp Lys Cys 1 5 10 34 10 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 34 Cys Pro Asp Trp Tyr Gln Ser TyrMet Cys 1 5 10 35 10 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 35 Cys Pro Asp Trp Tyr Ser Tyr Tyr Met Cys 15 10 36 10 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 36 Cys Pro Glu Trp Tyr Thr Asp Val Met Cys 1 5 10 3710 PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 37 Cys Pro Asp Trp Tyr Leu Asp Tyr Met Cys 1 5 10 38 10 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide38 Cys Pro Glu Trp Tyr Leu Asp Tyr Met Cys 1 5 10 39 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 39 Cys ProAsp Trp Tyr Leu Pro Tyr Met Cys 1 5 10 40 10 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 40 Cys Pro Glu TrpTyr Leu Pro Tyr Met Cys 1 5 10 41 10 PRT Artificial Sequence Descriptionof Artificial Sequence Synthetic peptide 41 Cys Gln Asp Trp Trp Val GluLeu Trp Cys 1 5 10 42 10 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 42 Cys Pro Asp Trp Tyr Leu Pro TrpMet Cys 1 5 10 43 10 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 43 Cys Ala Cys Met Leu Arg Val Val His Cys 15 10 44 10 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 44 Cys Gln Arg Ala Gly Tyr Met Leu Ala Cys 1 5 10 4510 PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 45 Cys His Ala Asn Pro Val Trp Gly Glu Cys 1 5 10 46 10 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide46 Cys Phe Trp Ser Asp Trp Gly Gln Thr Cys 1 5 10 47 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 47 Cys ProHis Trp Thr Ser Tyr Tyr Met Cys 1 5 10 48 10 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 48 Cys Glu Thr LeuCys Gly Ala Cys Phe Cys 1 5 10 49 10 PRT Artificial Sequence Descriptionof Artificial Sequence Synthetic peptide 49 Cys Ala Thr Thr Ile Asn AspThr Leu Cys 1 5 10 50 10 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 50 Cys Leu Asn Tyr Pro His Pro ValPhe Cys 1 5 10 51 10 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 51 Cys Met Asp Gly Glu Met Ala Val Asp Cys 15 10 52 10 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 52 Cys Asn Met Gly Trp Met Ser Trp Pro Cys 1 5 10 5310 PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 53 Cys Glu Thr Tyr Ala Asp Trp Leu Gly Cys 1 5 10 54 10 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide54 Cys Asp Pro Trp Met Phe Phe Asp Met Cys 1 5 10 55 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 55 Cys AspPro Trp Ile Trp Tyr Asp Leu Cys 1 5 10 56 10 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 56 Cys Asp Pro TrpIle Met Tyr Asp Arg Cys 1 5 10 57 10 PRT Artificial Sequence Descriptionof Artificial Sequence Synthetic peptide 57 Cys Asp Pro Trp Val Phe PheAsp Ile Cys 1 5 10 58 10 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 58 Cys Asp Pro Trp Thr Tyr Tyr AspLeu Cys 1 5 10 59 10 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 59 Cys Asp Pro Trp Ile Phe Tyr Asp Arg Cys 15 10 60 10 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 60 Cys Asp Pro Trp Leu Phe Tyr Asp Leu Cys 1 5 10 6110 PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 61 Cys Asp Pro Trp Val Trp Tyr Asp Leu Cys 1 5 10 62 10 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide62 Cys Asp Pro Trp Ile Phe Phe Asp Arg Cys 1 5 10 63 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 63 Cys AspPro Trp Met Phe Phe Asp Gln Cys 1 5 10 64 10 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 64 Cys Asp Pro TrpLeu Trp Tyr Asp Arg Cys 1 5 10 65 10 PRT Artificial Sequence Descriptionof Artificial Sequence Synthetic peptide 65 Cys Asp Val Trp Val Trp TyrAsp Gln Cys 1 5 10 66 10 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 66 Cys Asp Pro Trp Ile Tyr Tyr AspLeu Cys 1 5 10 67 10 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 67 Cys Val Pro Trp Thr Leu Phe Asp Leu Cys 15 10 68 10 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 68 Cys Pro Ala Trp Tyr Leu Glu Tyr Met Cys 1 5 10 6910 PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 69 Cys Pro Asp Trp Tyr Leu Glu Tyr Met Cys 1 5 10 70 10 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide70 Cys Lys Tyr Trp Gln Trp Phe Asp Lys Cys 1 5 10 71 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 71 Cys AspHis Trp Met Trp Tyr Asp Lys Cys 1 5 10 72 12 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 72 Gly Cys Asn ArgGlu Ile Glu Ala Met Cys Cys Gly 1 5 10 73 12 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 73 Gly Cys Pro GluTrp Tyr Thr Asp Val Met Cys Gly 1 5 10 74 16 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 74 Asn Trp Tyr CysMet Asp Gly Glu Met Ala Val Asp Cys Glu Ala Thr 1 5 10 15 75 16 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide75 Trp Gln Ser Cys Asn Met Gly Trp Met Ser Trp Pro Cys Tyr Phe Val 1 510 15 76 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 76 His Glu Leu Cys Glu Thr Tyr Ala Asp Trp Leu Gly CysVal Glu Trp 1 5 10 15 77 14 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 77 Pro Cys Asp Pro Trp Met Phe PheAsp Met Cys Glu Arg Trp 1 5 10 78 16 PRT Artificial Sequence Descriptionof Artificial Sequence Synthetic peptide 78 Leu Arg Gly Cys Asp Pro TrpIle Trp Tyr Asp Leu Cys Pro Ala Val 1 5 10 15 79 16 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 79 Gly TyrLeu Cys Asp Pro Trp Ile Phe Tyr Asp Arg Cys Leu Gly Phe 1 5 10 15 80 16PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 80 Arg Phe Ala Cys Asp Pro Trp Val Phe Phe Asp Ile Cys Gly TyrTrp 1 5 10 15 81 16 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 81 Gly Tyr Trp Cys Asp Pro Trp Thr Tyr TyrAsp Leu Cys Leu Thr Ala 1 5 10 15 82 16 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 82 Met Trp Thr CysAsp Pro Trp Ile Phe Tyr Asp Arg Cys Phe Leu Asn 1 5 10 15 83 16 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide83 Gly Ser Ser Cys Asp Pro Trp Leu Phe Tyr Asp Leu Cys Leu Leu Asp 1 510 15 84 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 84 Gly Gly Gly Cys Asp Pro Trp Val Trp Tyr Asp Leu CysTrp Cys Asp 1 5 10 15 85 16 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 85 Tyr Thr Ser Cys Asp Pro Trp IlePhe Phe Asp Arg Cys Met Ser Val 1 5 10 15 86 16 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 86 Asp Pro Tyr CysAsp Pro Trp Met Phe Phe Asp Gln Cys Ala Tyr Leu 1 5 10 15 87 14 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide87 Arg Glu Phe Cys Asp Pro Trp Leu Trp Tyr Asp Arg Cys Leu 1 5 10 88 16PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 88 Asn Thr Gly Cys Asp Val Trp Val Trp Tyr Asp Gln Cys Phe AlaMet 1 5 10 15 89 16 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 89 Leu Val Phe Cys Asp Pro Trp Ile Tyr TyrAsp Leu Cys Met Asp Thr 1 5 10 15 90 12 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 90 Gly Cys Ser PheVal Gln Leu Asn Ser Ile Cys Gly 1 5 10 91 12 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 91 Gly Cys Pro AlaTrp Tyr Leu Glu Tyr Met Cys Gly 1 5 10 92 12 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 92 Gly Cys Pro AspTrp Tyr Leu Glu Tyr Met Cys Gly 1 5 10 93 12 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 93 Gly Cys Lys TyrTrp Gln Trp Phe Asp Lys Cys Gly 1 5 10 94 12 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 94 Gly Cys Asp HisTrp Met Trp Tyr Asp Lys Cys Gly 1 5 10 95 9 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 95 Ser Asn Glu SerGly Trp Val Trp Leu 1 5 96 9 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 96 Gln Ser Asn Ser Gly Trp Val TrpVal 1 5 97 9 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 97 Arg Thr Glu Ser Gly Trp Val Trp Thr 1 5 98 9 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide98 Arg Ala Asn Ser Gly Trp Val Trp Val 1 5 99 9 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 99 Tyr Asp Asn SerGly Trp Val Trp His 1 5 100 10 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 100 Leu Ser Asp Ser Gly Trp ValTrp Val Pro 1 5 10 101 15 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 101 Glu Gln Ser Asn Ser Gly TrpVal Trp Val Gly Gly Gly Gly Cys 1 5 10 15 102 11 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 102 Cys Glu Gln SerAsn Ser Gly Trp Val Trp Val 1 5 10 103 18 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 103 Glu Gln Ser AsnSer Gly Trp Val Trp Val Gly Gly Gly Gly Cys Lys 1 5 10 15 Lys Lys 104 15PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 104 Glu Gln Ser Asn Ser Gly Trp Val Trp Val Gly Lys Lys Lys Cys1 5 10 15 105 14 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 105 Glu Gln Ser Asn Ser Gly Trp Val Trp ValGly Lys Lys Lys 1 5 10 106 13 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 106 Lys Lys Lys Glu Gln Ser AsnSer Gly Trp Val Trp Val 1 5 10 107 18 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 107 Glu Gln Ser AsnSer Gly Trp Val Trp Val Gly Lys Lys Lys Ser Lys 1 5 10 15 Lys Lys 108 16PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 108 Glu Gln Ser Asn Ser Gly Trp Val Trp Val Gly Gly Cys Lys LysLys 1 5 10 15 109 20 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 109 Glu Gln Ser Asn Ser Gly Trp Val Trp ValGly Gly Gly Gly Gly Gly 1 5 10 15 Cys Lys Lys Lys 20 110 10 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide110 Ser Asn Glu Ser Gly Trp Val Trp Leu Pro 1 5 10 111 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 111 GluGln Ser Asn Ser Gly Trp Val Trp Val 1 5 10 112 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 112 SerArg Thr Glu Ser Gly Trp Val Trp Thr 1 5 10 113 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 113 GlnArg Ala Asn Ser Gly Trp Val Trp Val 1 5 10 114 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 114 AspTyr Asp Asn Ser Gly Trp Val Trp His 1 5 10 115 15 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 115 GluGln Ser Asn Ser Gly Trp Val Trp Val Gly Lys Lys Lys Lys 1 5 10 15 116 18PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 116 Glu Gln Ser Asn Ser Gly Trp Val Trp Val Gly Gly Gly Gly SerLys 1 5 10 15 Lys Lys 117 15 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 117 Glu Gln Ser Asn Ser Gly TrpVal Trp Val Gly Gly Gly Gly Ser 1 5 10 15 118 30 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 118 Glu Gln Ser AsnSer Gly Trp Val Trp Val Gly Gly Gly Gly Ser Glu 1 5 10 15 Gln Ser AsnSer Gly Trp Val Trp Val Gly Gly Gly Gly Ser 20 25 30 119 20 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide119 Arg Tyr Gln Ser Phe Glu Leu Ser Asp Ser Gly Trp Val Trp Val Pro 1 510 15 Val Ala Arg His 20 120 6 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 120 Glu Arg Asp Trp Phe Cys 1 5121 6 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 121 Glu Arg Asp Trp Gly Cys 1 5 122 6 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 122 GluArg Leu Trp Phe Cys 1 5 123 6 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 123 Glu Arg Ser Tyr Phe Cys 1 5124 6 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 124 Glu Arg Gly Trp Phe Cys 1 5 125 6 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 125 GluArg Glu Trp Phe Cys 1 5 126 6 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 126 Glu Arg Ala Trp Phe Cys 1 5127 6 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 127 Glu Arg Leu Tyr Phe Cys 1 5 128 6 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 128 GluArg Tyr Phe Met Cys 1 5 129 6 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 129 Glu Arg Leu Phe Leu Cys 1 5130 6 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 130 Glu Arg Ala Leu Met Cys 1 5 131 6 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 131 GluArg Asp Val Met Cys 1 5 132 6 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 132 Glu Arg Lys Trp Phe Cys 1 5133 10 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 133 Glu Thr Trp Gly Glu Arg Asp Trp Phe Cys 1 5 10 13410 PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 134 Glu Thr Trp Gly Glu Arg Asp Trp Gly Cys 1 5 10 135 10 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide135 Ser Thr Ala Glu Arg Leu Trp Phe Cys Gly 1 5 10 136 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 136 TyrGlu Thr Ala Glu Arg Ser Tyr Phe Cys 1 5 10 137 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 137 AlaAsp Asn Ala Glu Arg Gly Trp Phe Cys 1 5 10 138 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 138 GlnSer Asn Ser Glu Arg Glu Trp Phe Cys 1 5 10 139 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 139 SerThr Ser Glu Arg Ala Trp Phe Cys Gly 1 5 10 140 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 140 AlaSer Trp Ser Glu Arg Gly Trp Phe Cys 1 5 10 141 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 141 GluLeu Ser Ser Glu Arg Glu Trp Phe Cys 1 5 10 142 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 142 AspMet Gln Gly Glu Arg Gly Trp Phe Cys 1 5 10 143 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 143 SerSer Ser Glu Arg Ala Trp Phe Cys Gly 1 5 10 144 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 144 GlyAsn Met Arg Glu Arg Leu Tyr Phe Cys 1 5 10 145 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 145 GlnPro Asn Arg Glu Arg Tyr Phe Met Cys 1 5 10 146 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 146 SerVal Thr Arg Glu Arg Leu Phe Leu Cys 1 5 10 147 15 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 147 IlePro Leu Ser Glu Arg Ala Leu Met Cys Ser Ser Trp Asn Cys 1 5 10 15 148 15PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 148 Trp Ala Arg Ser Glu Arg Asp Val Met Cys Leu Ser Tyr Val Cys1 5 10 15 149 11 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 149 Gln Ser Asn Ser Glu Arg Glu Trp Phe CysGly 1 5 10 150 15 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 150 Gln Ser Asn Ser Glu Arg Glu Trp Phe CysGly Gly Gly Gly Ser 1 5 10 15 151 19 PRT Artificial Sequence Descriptionof Artificial Sequence Synthetic peptide 151 Asn Leu Glu Glu Ala Leu AlaGln Glu Arg Leu Trp Phe Cys Arg Ser 1 5 10 15 Gly Asn Cys 152 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide152 Asn Leu Glu Ser Tyr Glu Met Glu Glu Arg Lys Trp Phe Cys Lys Met 1 510 15 Phe Ser Cys 153 9 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 153 Asp Met Val Tyr Ala Tyr ProPro Trp 1 5 154 9 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 154 Glu Met Val Tyr Thr Val Pro Tyr Trp 1 5155 10 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 155 Asp Met Val Tyr Ala Tyr Pro Pro Trp Ser 1 5 10 15610 PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 156 Asp Glu Met Val Tyr Thr Val Pro Tyr Trp 1 5 10 157 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide157 Cys Glu Ser Arg Leu Val Glu Cys Ser Arg Met Cys 1 5 10 158 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide158 Cys Glu Thr Tyr Met Thr Tyr Val Tyr Trp Leu Cys 1 5 10 159 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide159 Cys Gly Glu Arg Leu Ala Glu Cys Ala Arg Leu Cys 1 5 10 160 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide160 Cys Glu Ser Arg Leu Arg Glu Cys Ser Met Leu Cys 1 5 10 161 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide161 Cys Glu Ala Arg Leu Ser Glu Cys Ser Arg Ile Cys 1 5 10 162 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide162 Cys Pro Ala Arg Leu Leu Glu Cys Ser Arg Met Cys 1 5 10 163 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide163 Cys Glu Ser Val Gly Val Gly Asp Trp Trp Ser Cys 1 5 10 164 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide164 Cys Glu Asp Arg Leu Val Glu Gly Pro Trp Val Cys 1 5 10 165 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide165 Cys Asn Asp Gln Phe Arg Thr Cys Val Asp Val Cys 1 5 10 166 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide166 Cys Arg Gly Glu Trp Trp Glu Leu Tyr His Pro Cys 1 5 10 167 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide167 Cys Glu Asp Thr Arg Thr Gly Trp Ala Trp Ser Cys 1 5 10 168 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide168 Cys Thr Trp Leu Ser Ser Gly Glu Leu Val Trp Cys 1 5 10 169 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide169 Cys Trp Pro Pro Val Cys Glu Val Ser Gly Ile Cys 1 5 10 170 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide170 Cys Ser Leu Ser Pro Ile Gln Leu Gln His Leu Cys 1 5 10 171 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide171 Cys Leu Ala Arg Leu Glu Glu Cys Ser Arg Phe Cys 1 5 10 172 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide172 Cys His Asn Ser Ser Pro Met Val Gly Val Thr Cys 1 5 10 173 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide173 Cys His Val Ser Pro Val Gln Ile Lys Ala Leu Cys 1 5 10 174 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide174 Cys Ala Ala Pro Ala Thr Ser Trp Phe Gln Tyr Cys 1 5 10 175 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide175 Cys Ala Ser Lys Leu His Glu Cys Ser Leu Arg Cys 1 5 10 176 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide176 Cys Glu Pro Met Asp Ser Asn Gly Ile Val Gln Cys 1 5 10 177 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide177 Cys Gln Tyr Ala Ser Ala Ala Asp Glu Gln Arg Cys 1 5 10 178 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide178 Cys Glu Tyr Trp Asp Glu Pro Ser Leu Ser Trp Cys 1 5 10 179 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide179 Cys Glu Arg Glu Cys Phe Gln Met Leu Glu Arg Cys 1 5 10 180 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide180 Cys Gly Met Ser Thr Asp Glu Leu Asp Glu Ile Cys 1 5 10 181 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide181 Cys Tyr Val Ser Pro Ser Thr Gly Leu Tyr Ser Cys 1 5 10 182 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide182 Cys Glu Ala Arg Leu Val Glu Cys Ser Arg Leu Cys 1 5 10 183 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide183 Cys Glu Ser Arg Leu Ser Glu Cys Ser Arg Met Cys 1 5 10 184 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide184 Cys Glu Leu Lys Leu Gln Glu Cys Ala Arg Arg Cys 1 5 10 185 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide185 Cys Glu Leu Lys Leu Gln Glu Ala Ala Arg Arg Cys 1 5 10 186 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide186 Cys Leu Glu Arg Leu Glu Glu Cys Ser Arg Phe Cys 1 5 10 187 14 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide187 Gly Gly Cys Glu Ser Arg Leu Val Glu Cys Ser Arg Met Cys 1 5 10 18814 PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 188 Gly Gly Cys Glu Thr Tyr Met Thr Tyr Val Tyr Trp Leu Cys 1 510 189 15 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 189 Glu Trp Leu Cys Glu Ser Val Gly Val Gly Asp TrpTrp Ser Cys 1 5 10 15 190 18 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 190 Tyr His Pro Cys Glu Asp ArgLeu Val Glu Gly Pro Trp Val Cys Cys 1 5 10 15 Arg Ser 191 18 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide191 Trp Leu Leu Cys Asn Asp Gln Phe Arg Thr Cys Val Asp Val Cys Asp 1 510 15 Asn Val 192 18 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 192 Ile Ala Glu Cys Arg Gly Glu Trp Trp GluLeu Tyr His Pro Cys Leu 1 5 10 15 Ala Ala 193 18 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 193 Thr Trp Tyr CysGlu Asp Thr Arg Thr Gly Trp Ala Trp Ser Cys Leu 1 5 10 15 Glu Leu 194 18PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 194 Gln Leu Asp Cys Thr Trp Leu Ser Ser Gly Glu Leu Val Trp CysSer 1 5 10 15 Asp Trp 195 18 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 195 Gln Phe Asp Cys Thr Trp LeuSer Ser Gly Glu Leu Val Trp Cys Ser 1 5 10 15 Asp Trp 196 13 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide196 Cys Trp Pro Pro Val Cys Glu Val Ser Gly Ile Cys Ser 1 5 10 197 14PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 197 Cys Gly Cys Ser Leu Ser Pro Ile Gln Leu Gln His Leu Cys 1 510 198 14 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 198 Cys Gly Cys His Val Ser Pro Val Gln Ile Lys AlaLeu Cys 1 5 10 199 13 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 199 Gly Cys His Val Ser Pro Val Gln Ile LysAla Leu Cys 1 5 10 200 18 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 200 Gly Thr Ser Cys Ala Ala ProAla Thr Ser Trp Phe Gln Tyr Cys Val 1 5 10 15 Leu Pro 201 18 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide201 Arg Met Asp Cys Ala Ser Lys Leu His Glu Cys Ser Leu Arg Cys Ala 1 510 15 Tyr Ala 202 18 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 202 Gly Val Val Cys Glu Pro Met Asp Ser AsnGly Ile Val Gln Cys Ser 1 5 10 15 Met Arg 203 18 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 203 Ile Asp Val CysGln Tyr Ala Ser Ala Ala Asp Glu Gln Arg Cys Leu 1 5 10 15 Arg Ile 204 18PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 204 Asn Val Leu Cys Glu Tyr Trp Asp Glu Pro Ser Leu Ser Trp CysLeu 1 5 10 15 Ser Ser 205 14 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 205 Cys Gln Cys Glu Arg Glu CysPhe Gln Met Leu Glu Arg Cys 1 5 10 206 18 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 206 Phe Cys Ser CysGly Met Ser Thr Asp Glu Leu Asp Glu Ile Cys Ala 1 5 10 15 Ile Trp 207 18PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 207 Glu Glu Val Cys Tyr Val Ser Pro Ser Thr Gly Leu Tyr Ser CysTyr 1 5 10 15 Asp Gln 208 17 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 208 Leu Leu Asp Ile Cys Glu LeuLys Leu Gln Glu Cys Ala Arg Arg Cys 1 5 10 15 Asn 209 20 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 209 GlyGly Gly Leu Leu Asp Ile Cys Glu Leu Lys Leu Gln Glu Cys Ala 1 5 10 15Arg Arg Cys Asn 20 210 23 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 210 Gly Arg Thr Gly Gly Gly LeuLeu Asp Ile Cys Glu Leu Lys Leu Gln 1 5 10 15 Glu Cys Ala Arg Arg CysAsn 20 211 27 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 211 Leu Gly Ile Glu Gly Arg Thr Gly Gly Gly Leu LeuAsp Ile Cys Glu 1 5 10 15 Leu Lys Leu Gln Glu Cys Ala Arg Arg Cys Asn 2025 212 17 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 212 Leu Leu Asp Ile Cys Glu Leu Lys Leu Gln Glu AlaAla Arg Arg Cys 1 5 10 15 Asn 213 18 PRT Artificial Sequence Descriptionof Artificial Sequence Synthetic peptide 213 Lys Leu Leu Asp Ile Cys GluLeu Lys Leu Gln Glu Ala Ala Arg Arg 1 5 10 15 Cys Asn 214 9 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide214 Glu Glu Lys Leu Arg Glu Cys Ala Arg 1 5 215 9 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 215 GluAla Arg Leu Ala Glu Cys Ala Arg 1 5 216 9 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 216 Cys Met Lys LeuMet Glu Cys Ala Arg 1 5 217 9 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 217 Glu Leu Arg Leu Arg Glu CysAla His 1 5 218 9 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 218 Glu Ala Lys Leu His Glu Cys Ala Arg 1 5219 9 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 219 Glu Leu Lys Leu Ala Glu Cys Ala Arg 1 5 220 9 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide220 Glu Ala Arg Leu Glu Glu Cys Ala Arg 1 5 221 9 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 221 GluAla Lys Leu Arg Glu Cys Ala Arg 1 5 222 9 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 222 Glu Leu Arg LeuAla Glu Cys Ala Arg 1 5 223 9 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 223 Glu Ser Arg Leu Ala Glu CysAla Arg 1 5 224 9 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 224 Glu Ala Lys Leu Val Glu Cys Ala Arg 1 5225 9 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 225 Glu Ser Arg Leu Arg Glu Cys Ala Arg 1 5 226 9 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide226 Glu Ala Lys Leu Ala Glu Cys Ala Arg 1 5 227 9 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 227 GlnTrp Arg Leu Glu Glu Cys Ala Arg 1 5 228 9 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 228 Gln Leu Arg LeuGlu Glu Cys Ala Arg 1 5 229 9 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 229 Glu Leu Arg Leu Glu Glu CysAla Arg 1 5 230 9 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 230 Glu Ala Lys Leu Leu Glu Cys Ala Arg 1 5231 9 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 231 Glu Ala Arg Ala Gly Val Cys Ala Gly 1 5 232 9 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide232 Glu Ala Lys Ala Gly Val Cys Ala Gly 1 5 233 9 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 233 ValAla Arg Leu Glu Glu Cys Ala Arg 1 5 234 9 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 234 Glu Leu Lys LeuAsp Glu Cys Ala Arg 1 5 235 9 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 235 Glu Trp Arg Leu Gln Glu CysAla Arg 1 5 236 9 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 236 Glu Ala Lys Leu Ser Glu Cys Ala Arg 1 5237 9 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 237 Glu Ala Arg Leu Ser Glu Cys Ala Arg 1 5 238 9 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide238 Glu Leu Lys Leu Leu Glu Cys Ala Arg 1 5 239 9 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 239 GluLeu Arg Leu Gln Glu Cys Gly Arg 1 5 240 9 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 240 Glu Gln Lys LeuAla Glu Cys Ala Arg 1 5 241 9 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 241 Glu Leu Arg Leu Gln Glu CysAla Arg 1 5 242 9 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 242 Glu Leu Lys Leu Glu Glu Cys Ala Arg 1 5243 9 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 243 Glu Ser Arg Leu Glu Glu Cys Ala Arg 1 5 244 9 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide244 Glu Ala Thr Val Gln Glu Cys Ala Arg 1 5 245 9 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 245 GluLeu Lys Leu Gln Glu Cys Ala Arg 1 5 246 9 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 246 Tyr Ser Arg LeuGlu Glu Cys Gly Arg 1 5 247 9 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 247 Glu Leu Arg Leu Arg Glu CysAla Leu 1 5 248 9 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 248 Glu Ala Arg Leu Leu Glu Cys Ala Arg 1 5249 9 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 249 Glu Ser Arg Leu Leu Glu Cys Ala Arg 1 5 250 9 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide250 Val Leu Lys Leu Glu Glu Cys Ala Arg 1 5 251 9 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 251 GluSer Lys Leu Ala Glu Cys Ala Arg 1 5 252 9 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 252 Glu Ser Lys LeuArg Glu Cys Ala Arg 1 5 253 9 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 253 Glu Tyr Lys Leu Gly Glu CysAla Arg 1 5 254 9 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 254 Glu Ser Arg Leu Gln Glu Cys Ala Arg 1 5255 9 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 255 Gln Ala Arg Leu Ala Glu Cys Ala Arg 1 5 256 9 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide256 Glu Leu Lys Lys Gln Glu Cys Ala Arg 1 5 257 9 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 257 GluSer Arg Leu Ser Glu Cys Ala Arg 1 5 258 9 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 258 Glu Ala Arg LeuGlu Glu Cys Gly Arg 1 5 259 9 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 259 Glu Ser Arg Leu Ala Glu CysGly Arg 1 5 260 9 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 260 Glu Trp Arg Leu Glu Glu Cys Ala Arg 1 5261 9 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 261 Glu Ala Arg Leu Ser Glu Cys Gly Arg 1 5 262 9 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide262 Ala Ala Arg Leu Ala Glu Cys Ala Arg 1 5 263 9 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 263 GluTrp Lys Leu Ala Glu Cys Ala Arg 1 5 264 9 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 264 Glu Ser Lys LeuGlu Glu Cys Ala Arg 1 5 265 9 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 265 Asp Val Lys Leu Ala Glu CysAla Arg 1 5 266 9 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 266 Glu Leu Gln Leu Glu Glu Cys Ala Arg 1 5267 9 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 267 Glu Tyr Lys Leu Ala Ser Cys Ala Arg 1 5 268 16 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide268 Arg Leu Ser Ile Cys Glu Glu Lys Leu Arg Glu Cys Ala Arg Gly Cys 1 510 15 269 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 269 Pro Leu Thr Thr Cys Glu Ala Arg Leu Ala Glu CysAla Arg Gln Leu 1 5 10 15 270 14 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 270 Leu Ala Leu Cys Met Lys LeuMet Glu Cys Ala Arg Arg Tyr 1 5 10 271 16 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 271 Glu Leu Val MetCys Glu Leu Arg Leu Arg Glu Cys Ala His Arg Ala 1 5 10 15 272 16 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide272 Pro Leu Ala Arg Cys Glu Ala Lys Leu His Glu Cys Ala Arg Gln Leu 1 510 15 273 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 273 Leu Leu Ser Val Cys Glu Leu Lys Leu Ala Glu CysAla Arg Ser Lys 1 5 10 15 274 16 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 274 Arg Leu Glu Trp Cys Glu AlaArg Leu Glu Glu Cys Ala Arg Arg Cys 1 5 10 15 275 16 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 275 ArgLeu Arg Val Val Glu Ala Lys Leu Arg Glu Cys Ala Arg Gly Arg 1 5 10 15276 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 276 Cys Val Ala His Leu Glu Leu Arg Leu Ala Glu CysAla Arg Gln Ile 1 5 10 15 277 16 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 277 His Leu Ala Arg Cys Glu SerArg Leu Ala Glu Cys Ala Arg Gln Leu 1 5 10 15 278 16 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 278 ArgLeu Ala Leu Leu Glu Ala Lys Leu Val Glu Cys Ala Arg Arg Leu 1 5 10 15279 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 279 Asp Leu Phe Ser Leu Glu Ser Arg Leu Arg Glu CysAla Arg Arg Val 1 5 10 15 280 16 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 280 Ala Val Pro Val Leu Glu AlaLys Leu Ala Glu Cys Ala Arg Arg Phe 1 5 10 15 281 16 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 281 TyrLeu Gln Gln Leu Gln Trp Arg Leu Glu Glu Cys Ala Arg Gly Met 1 5 10 15282 17 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 282 Tyr Leu Glu Leu Cys Gln Leu Arg Leu Glu Glu CysAla Arg Gln Phe 1 5 10 15 Asn 283 16 PRT Artificial Sequence Descriptionof Artificial Sequence Synthetic peptide 283 Glu Leu His Ile Cys Glu LeuArg Leu Glu Glu Cys Ala Arg Gly Arg 1 5 10 15 284 16 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 284 ArgVal Ala Arg Cys Glu Leu Arg Leu Ala Glu Cys Ala Arg Lys Ser 1 5 10 15285 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 285 Tyr Leu Glu Val Leu Glu Ser Arg Leu Ala Glu CysAla Arg Trp Lys 1 5 10 15 286 11 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 286 Glu Ala Lys Leu Leu Glu CysAla Arg Ala Arg 1 5 10 287 18 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 287 Glu Leu Ser Leu Cys Glu AlaArg Ala Gly Val Cys Ala Gly Ser Val 1 5 10 15 Thr Lys 288 18 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide288 Glu Leu Ser Leu Cys Glu Ala Lys Ala Gly Val Cys Ala Gly Ser Val 1 510 15 Thr Lys 289 16 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 289 Ala Leu Trp Gln Cys Val Ala Arg Leu GluGlu Cys Ala Arg Ser Arg 1 5 10 15 290 16 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 290 Cys Leu Lys SerCys Glu Leu Lys Leu Asp Glu Cys Ala Arg Arg Met 1 5 10 15 291 16 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide291 Ala Leu Gln Thr Cys Glu Trp Arg Leu Gln Glu Cys Ala Arg Ser Arg 1 510 15 292 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 292 Tyr Ile Ser Gln Cys Glu Ala Lys Leu Ala Glu CysAla Arg Leu Tyr 1 5 10 15 293 16 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 293 Glu Leu Ser Ser Cys Glu AlaLys Leu Ser Glu Cys Ala Arg Arg Trp 1 5 10 15 294 16 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 294 GluLeu Ser Ser Cys Glu Ala Arg Leu Ser Glu Cys Ala Arg Arg Trp 1 5 10 15295 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 295 Gln Leu Leu Gln Cys Glu Leu Lys Leu Leu Glu CysAla Arg Gln Gly 1 5 10 15 296 16 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 296 Glu Leu Leu Arg Cys Glu AlaArg Leu Ala Glu Cys Ala Arg Gly Cys 1 5 10 15 297 17 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 297 GlnLeu Arg Gln Cys Glu Leu Arg Leu Gln Glu Cys Gly Arg His Gly 1 5 10 15Asn 298 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 298 Pro Leu Thr Ser Cys Glu Gln Lys Leu Ala Glu CysAla Arg Arg Phe 1 5 10 15 299 16 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 299 Leu Leu Gly Met Cys Glu LeuArg Leu Gln Glu Cys Ala Arg Ala Lys 1 5 10 15 300 16 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 300 GluLeu Ser Arg Cys Glu Leu Lys Leu Glu Glu Cys Ala Arg Gly Met 1 5 10 15301 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 301 Asp Cys Arg Pro Cys Glu Ser Arg Leu Glu Glu CysAla Arg Arg Leu 1 5 10 15 302 16 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 302 Arg Leu Ser Val Cys Glu AlaArg Leu Glu Glu Cys Ala Arg Gln Leu 1 5 10 15 303 16 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 303 ProLeu Lys Met Cys Glu Ala Thr Val Gln Glu Cys Ala Arg Leu Ile 1 5 10 15304 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 304 Leu Leu Leu Phe Cys Glu Ala Arg Leu Ser Glu CysAla Arg His Val 1 5 10 15 305 16 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 305 Ser Leu Ser Met Cys Glu AlaArg Leu Ala Glu Cys Ala Arg Leu Leu 1 5 10 15 306 17 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 306 ProLeu Phe Ser Cys Glu Leu Lys Leu Gln Glu Cys Ala Arg Arg Cys 1 5 10 15Asn 307 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 307 Ser Leu Glu Arg Cys Tyr Ser Arg Leu Glu Glu CysGly Arg Arg Ile 1 5 10 15 308 17 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 308 Pro Leu Thr Ser Cys Glu LeuArg Leu Arg Glu Cys Ala Leu Arg Ser 1 5 10 15 Asn 309 16 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 309 LysLeu Ala Ala Cys Glu Leu Lys Leu Ala Glu Cys Ala Arg Arg Trp 1 5 10 15310 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 310 Lys Leu Ala Ala Cys Glu Leu Arg Leu Ala Glu CysAla Arg Arg Trp 1 5 10 15 311 16 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 311 Ala Leu Thr Arg Cys Glu LeuArg Leu Ala Glu Cys Ala Arg Lys Ile 1 5 10 15 312 16 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 312 LeuLeu Gln Gln Cys Glu Leu Lys Leu Ala Glu Cys Ala Arg Ser Ile 1 5 10 15313 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 313 Gln Leu Trp Gln Cys Glu Ala Arg Leu Leu Glu CysAla Arg Arg Ser 1 5 10 15 314 16 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 314 Arg Leu Arg Leu Cys Glu SerArg Leu Leu Glu Cys Ala Arg Ser Leu 1 5 10 15 315 17 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 315 GlnLeu Glu Thr Cys Val Leu Lys Leu Glu Glu Cys Ala Arg Arg Cys 1 5 10 15Asn 316 18 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 316 Ala Leu Ser Gln Cys Glu Leu Arg Leu Ala Glu CysAla Arg Ser Val 1 5 10 15 Thr Lys 317 11 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 317 Glu Leu Lys LeuAla Glu Cys Ala Arg Arg Ser 1 5 10 318 16 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 318 Ala Leu Ser ArgCys Glu Ser Lys Leu Ala Glu Cys Ala Arg Arg Gln 1 5 10 15 319 16 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide319 Leu Met Ser Thr Cys Glu Ser Lys Leu Arg Glu Cys Ala Arg Ser Leu 1 510 15 320 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 320 Ser Leu Gln Arg Cys Glu Tyr Lys Leu Gly Glu CysAla Arg Ser Leu 1 5 10 15 321 17 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 321 Arg Leu Glu Leu Leu Glu SerArg Leu Gln Glu Cys Ala Arg Gln Leu 1 5 10 15 Asn 322 17 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 322 GlnMet Glu Trp Cys Gln Ala Arg Leu Ala Glu Cys Ala Arg Cys Cys 1 5 10 15Asn 323 17 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 323 Pro Leu Phe Ser Cys Glu Leu Lys Lys Gln Glu CysAla Arg Arg Cys 1 5 10 15 Asn 324 16 PRT Artificial Sequence Descriptionof Artificial Sequence Synthetic peptide 324 Leu Leu Asp Lys Cys Glu SerArg Leu Ser Glu Cys Ala Arg Arg Leu 1 5 10 15 325 16 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 325 LeuLeu Ala Arg Cys Glu Ala Arg Leu Glu Glu Cys Gly Arg Gln Cys 1 5 10 15326 15 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 326 Asp Leu Leu Tyr Cys Glu Ser Arg Leu Ala Glu CysGly Arg Met 1 5 10 15 327 16 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 327 Ala Leu Gln Met Cys Glu TrpArg Leu Glu Glu Cys Ala Arg Arg Leu 1 5 10 15 328 16 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 328 LeuLeu Thr Met Cys Glu Ala Arg Leu Ser Glu Cys Gly Arg Arg Leu 1 5 10 15329 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 329 Ala Leu Trp Arg Cys Glu Ser Arg Leu Ala Glu CysAla Arg Arg Ser 1 5 10 15 330 16 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 330 Leu Leu Ala Thr Cys Ala AlaArg Leu Ala Glu Cys Ala Arg Gln Leu 1 5 10 15 331 15 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 331 LeuGln Thr Cys Glu Trp Lys Leu Ala Glu Cys Ala Arg Ser Asn 1 5 10 15 332 16PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 332 Pro Leu Arg Ser Cys Glu Ser Lys Leu Glu Glu Cys Ala Arg GlnLeu 1 5 10 15 333 16 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 333 Cys Leu Arg Ala Leu Asp Val Lys Leu AlaGlu Cys Ala Arg His Leu 1 5 10 15 334 16 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 334 Arg Leu Lys ThrLeu Glu Leu Gln Leu Glu Glu Cys Ala Arg Arg Ser 1 5 10 15 335 16 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide335 Lys Leu Arg Asp Val Glu Leu Lys Leu Ala Glu Cys Ala Arg Arg Ser 1 510 15 336 16 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 336 Ser Leu Gln Arg Cys Glu Tyr Lys Leu Ala Ser CysAla Arg Ser Leu 1 5 10 15 337 16 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 337 Arg Leu Ala Arg Cys Glu LeuArg Leu Ala Glu Cys Ala Arg Lys Ser 1 5 10 15 338 17 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 338 AspLeu Trp Tyr Leu Glu Ser Lys Leu Glu Glu Cys Ala Arg Arg Cys 1 5 10 15Asn 339 18 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 339 Asp Leu Trp Tyr Leu Glu Ser Lys Leu Glu Glu CysAla Arg Arg Ala 1 5 10 15 Asn Gly 340 18 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 340 Asp Leu Trp TyrLeu Glu Ser Lys Leu Glu Glu Cys Ala Arg Arg Cys 1 5 10 15 Asn Gly 341 16PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 341 Lys Gln Arg Glu Leu Glu Leu Lys Leu Ala Glu Cys Ala Arg ArgSer 1 5 10 15 342 17 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 342 Gln Met Gln Glu Trp Cys Ala Arg Leu AlaGlu Cys Ala Arg Cys Cys 1 5 10 15 Asn 343 17 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 343 Leu Leu Asp IleCys Glu Leu Lys Leu Gln Glu Cys Ala Arg Arg Ala 1 5 10 15 Asn 344 10 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide344 Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp 1 5 10 345 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 345 AlaGlu Arg Tyr Ala Glu Glu Arg Glu Gly 1 5 10 346 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 346 AlaGlu Arg Met Ala Glu Glu Arg Arg Trp 1 5 10 347 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 347 AlaGlu Arg Lys Ala Glu Glu Arg Arg Arg 1 5 10 348 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 348 AlaHis Arg Asn Ala Glu Glu Arg Arg Trp 1 5 10 349 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 349 AlaGlu Arg Lys Ser Glu Asp Trp Arg Trp 1 5 10 350 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 350 AlaGlu Arg Lys Ala Glu Glu Lys Arg Arg 1 5 10 351 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 351 AlaGlu Arg Gln Ala Glu Thr Arg Arg Trp 1 5 10 352 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 352 AlaGlu Arg Asn Ala Glu Glu Arg Arg Trp 1 5 10 353 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 353 AlaGlu Arg Gln Ala Glu Glu Arg Arg Trp 1 5 10 354 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 354 AlaGlu Arg Arg Ala Glu Glu Arg Arg Trp 1 5 10 355 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 355 AlaGlu Arg Asp Ala Glu Gln Arg Arg Trp 1 5 10 356 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 356 AlaGlu Arg Ile Ala Glu Glu Arg Arg Trp 1 5 10 357 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 357 AlaGlu Arg Ser Ala Glu Glu Arg Arg Trp 1 5 10 358 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 358 AlaGlu Arg Lys Ala Glu Glu Leu Arg Trp 1 5 10 359 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 359 AlaGlu Arg Lys Ala Glu Glu Ser Arg Trp 1 5 10 360 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 360 GluGlu Arg Lys Ala Glu Glu Arg Arg Trp 1 5 10 361 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 361 AlaAsp Gly Lys Ala Glu Glu Arg Arg Trp 1 5 10 362 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 362 AlaAsp Gly Lys Ala Glu Glu Leu Arg Trp 1 5 10 363 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 363 AlaAsp Gly Met Pro Glu Glu Arg Arg Trp 1 5 10 364 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 364 AlaAsp Gly Glu Ala Glu Lys Arg Arg Trp 1 5 10 365 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 365 AlaAsp Gly Asn Ala Glu Glu Arg Arg Trp 1 5 10 366 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 366 AlaAsp Gly Glu Ala Glu Lys Ala Arg Trp 1 5 10 367 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 367 AlaGlu Gly Glu Ala Glu Lys Ala Arg Trp 1 5 10 368 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 368 GlyGlu Arg Lys Ala Glu Glu Arg Arg Trp 1 5 10 369 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 369 AlaGlu Arg Glu Ala Glu Glu Arg Arg Trp 1 5 10 370 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 370 AlaAsp Gly Glu Ala Glu Ala Arg Arg Trp 1 5 10 371 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 371 AlaAsp Gly Arg Ala Glu Glu Ala Arg Trp 1 5 10 372 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 372 AlaGlu Gly Arg Ala Glu Glu Ala Arg Trp 1 5 10 373 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 373 AlaGlu Arg Glu Ala Glu Lys Ala Arg Trp 1 5 10 374 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 374 AlaGlu Arg Lys Ala Glu Glu Gln Arg Trp 1 5 10 375 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 375 AlaGlu Arg Asp Ala Glu Lys Arg Arg Trp 1 5 10 376 10 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 376 AlaGlu Arg Glu Ala Glu Lys Leu Arg Trp 1 5 10 377 19 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 377 MetLeu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Phe Asn Thr His 1 5 10 15Gly Arg Glu 378 20 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 378 Met Leu Ala Glu Arg Lys Ala Glu Glu ArgArg Trp Phe Asn Thr His 1 5 10 15 Gly Arg Glu Lys 20 379 22 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide379 Gly Gly Gly Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Phe 1 510 15 Asn Thr His Gly Arg Glu 20 380 20 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 380 Cys Met Leu AlaGlu Arg Lys Ala Glu Glu Arg Arg Trp Phe Asn Thr 1 5 10 15 His Gly ArgGlu 20 381 21 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 381 Cys Met Leu Ala Glu Arg Lys Ala Glu Glu Arg ArgTrp Phe Asn Thr 1 5 10 15 His Gly Arg Glu Lys 20 382 19 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 382 MetLeu Ala Glu Arg Tyr Ala Glu Glu Arg Glu Gly Phe Asn Met Gln 1 5 10 15Trp Arg Glu 383 17 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 383 Met Leu Ala Glu Arg Met Ala Glu Glu ArgArg Trp Phe Arg Arg Met 1 5 10 15 Gly 384 19 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 384 Ile Val Ala GluArg Lys Ala Glu Glu Arg Arg Arg Leu Asn Thr Glu 1 5 10 15 Gly His Glu385 18 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 385 Ile Leu Ala His Arg Asn Ala Glu Glu Arg Arg TrpPhe Gln Lys His 1 5 10 15 Gly Arg 386 19 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 386 Met Leu Ala GluArg Lys Ser Glu Asp Trp Arg Trp Leu Lys Thr His 1 5 10 15 Gly Arg Asp387 19 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 387 Met Leu Ala Glu Arg Lys Ala Glu Glu Lys Arg ArgLeu Lys Thr Gln 1 5 10 15 Gly Arg Glu 388 21 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 388 Ile Leu Ala GluArg Gln Ala Glu Thr Arg Arg Trp Met Arg Asn Ala 1 5 10 15 Gly Ser ValThr Lys 20 389 18 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 389 Met Leu Ala Glu Arg Asn Ala Glu Glu ArgArg Trp Leu Lys Arg Gln 1 5 10 15 Cys Gly 390 19 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 390 Met Leu Ala GluArg Gln Ala Glu Glu Arg Arg Trp Leu Lys Met His 1 5 10 15 Gly Gly Glu391 19 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 391 Met Leu Ala Glu Arg Arg Ala Glu Glu Arg Arg TrpLeu Lys Thr Gln 1 5 10 15 Gly Gly Asp 392 19 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 392 Met Leu Ala GluArg Gln Ala Glu Glu Arg Arg Trp Leu Lys Thr Gln 1 5 10 15 Gly Arg Asp393 19 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 393 Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg TrpPhe Lys Thr His 1 5 10 15 Gly Arg Glu 394 19 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 394 Met Leu Ala GluArg Lys Ala Glu Glu Arg Arg Trp Phe Asn Asn Gln 1 5 10 15 Gly Arg Glu395 19 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 395 Met Pro Ala Glu Arg Asp Ala Glu Gln Arg Arg TrpLeu Lys Thr His 1 5 10 15 Gly Arg Glu 396 18 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 396 Ile Leu Ala GluArg Ile Ala Glu Glu Arg Arg Trp Leu Lys Thr Gln 1 5 10 15 Gly Arg 397 19PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 397 Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Leu Gln ThrHis 1 5 10 15 Gly Arg Glu 398 19 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 398 Ile Leu Ala Glu Arg Ser AlaGlu Glu Arg Arg Trp Leu Lys Thr Gln 1 5 10 15 Gly Arg Glu 399 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide399 Leu Leu Ala Glu Arg Lys Ala Glu Glu Leu Arg Trp Leu Lys Thr His 1 510 15 Gly Arg Glu 400 19 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 400 Met Leu Ala Glu Arg Lys AlaGlu Glu Arg Arg Trp Leu Gln Thr His 1 5 10 15 Gly Arg Glu 401 12 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide401 Met Leu Ala Glu Arg Asn Ala Glu Glu Arg Arg Trp 1 5 10 402 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide402 Met Phe Ala Glu Arg Lys Ala Glu Glu Ser Arg Trp Leu Gln Ser Gln 1 510 15 Gly Arg Glu 403 18 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 403 Met Leu Glu Glu Arg Lys AlaGlu Glu Arg Arg Trp Leu Lys Thr His 1 5 10 15 Gly Arg 404 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide404 Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Leu Lys Met Gln 1 510 15 Gly Arg Glu 405 19 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 405 Met Leu Ala Glu Arg Asn AlaGlu Glu Arg Arg Trp Phe Tyr Thr His 1 5 10 15 Gly Arg Glu 406 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide406 Met Leu Ala Asp Gly Lys Ala Glu Glu Arg Arg Trp Leu Lys Thr His 1 510 15 Gly Leu Asp 407 19 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 407 Met Ile Ala Asp Gly Lys AlaGlu Glu Arg Arg Trp Leu Lys Thr His 1 5 10 15 Gly Arg Asp 408 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide408 Met Leu Ala Asp Gly Lys Ala Glu Glu Leu Arg Trp Leu Lys Thr Gln 1 510 15 Gly Ser Asp 409 19 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 409 Met Leu Ala Glu Arg Asn AlaGlu Glu Arg Arg Trp Leu Lys Thr His 1 5 10 15 Gly Arg Asp 410 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide410 Met Leu Ala Asp Gly Lys Ala Glu Glu Leu Arg Trp Leu Lys Thr Gln 1 510 15 Gly Arg Glu 411 19 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 411 Ile Leu Ala Asp Gly Lys AlaGlu Glu Arg Arg Trp Leu Lys Thr His 1 5 10 15 Gly Arg Asp 412 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide412 Met Leu Ala Asp Gly Met Pro Glu Glu Arg Arg Trp Leu Gln Thr His 1 510 15 Gly Arg Asp 413 19 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 413 Met Leu Ala Asp Gly Glu AlaGlu Lys Arg Arg Trp Leu Asn Thr His 1 5 10 15 Gly Arg Asp 414 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide414 Met Leu Ala Asp Gly Asn Ala Glu Glu Arg Arg Trp Leu Met Thr His 1 510 15 Gly Arg Asp 415 19 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 415 Met Leu Ala Asp Gly Glu AlaGlu Lys Ala Arg Trp Leu Lys Thr Gln 1 5 10 15 Gly Arg Glu 416 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide416 Met Leu Ala Glu Gly Glu Ala Glu Lys Ala Arg Trp Leu Lys Thr Gln 1 510 15 Gly Arg Glu 417 19 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 417 Met Leu Ala Asp Gly Lys AlaGlu Glu Arg Arg Trp Leu Lys Thr Gln 1 5 10 15 Gly Arg Glu 418 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide418 Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Leu Ser Ala His 1 510 15 Val Arg Glu 419 19 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 419 Leu Leu Gly Glu Arg Lys AlaGlu Glu Arg Arg Trp Tyr Lys Thr His 1 5 10 15 Ala Arg Glu 420 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide420 Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Leu Met Thr His 1 510 15 Gly His Asp 421 19 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 421 Met Leu Ala Glu Arg Lys AlaGlu Glu Arg Arg Trp Leu Lys Ser Gln 1 5 10 15 Cys Leu Glu 422 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide422 Leu Leu Ala Glu Arg Glu Ala Glu Glu Arg Arg Trp Phe Lys Thr His 1 510 15 Gly Arg Glu 423 19 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 423 Met Leu Ala Asp Gly Glu AlaGlu Ala Arg Arg Trp Phe Asn Met His 1 5 10 15 Gly Arg Glu 424 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide424 Met Leu Ala Asp Gly Arg Ala Glu Glu Ala Arg Trp Leu Lys Thr Gln 1 510 15 Gly Ser Glu 425 19 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 425 Met Leu Ala Glu Gly Arg AlaGlu Glu Ala Arg Trp Leu Lys Thr Gln 1 5 10 15 Gly Ser Glu 426 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide426 Met Leu Ala Glu Arg Glu Ala Glu Lys Ala Arg Trp Leu Lys Thr Gln 1 510 15 Gly Arg Glu 427 19 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 427 Met Met Ala Glu Arg Lys AlaGlu Glu Gln Arg Trp Phe Asp Ile His 1 5 10 15 Gly Arg Asp 428 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide428 Leu Thr Ala Glu Arg Asp Ala Glu Lys Arg Arg Trp Leu Leu Thr His 1 510 15 Gly Gly Glu 429 19 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 429 Met Leu Ala Glu Arg Gln AlaGlu Glu Arg Arg Trp Leu Lys Ser Gln 1 5 10 15 Arg Gly Glu 430 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide430 Leu Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Phe Ala Thr His 1 510 15 Gly Arg Asp 431 19 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 431 Met Leu Ala Glu Arg Glu AlaGlu Lys Leu Arg Trp Leu Lys Ser Gln 1 5 10 15 Glu Arg Ala 432 19 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide432 Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Leu Lys Thr His 1 510 15 Gly Gly Glu 433 10 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 433 Cys Thr Trp Thr Asp Leu GluSer Val Tyr 1 5 10 434 10 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 434 His Thr Thr Asn Glu Gln PhePhe Met Cys 1 5 10 435 10 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 435 Asp Thr Trp Leu Glu Leu GluSer Arg Tyr 1 5 10 436 10 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 436 His Asn Ser Ser Pro Met ValGly Val Thr 1 5 10 437 10 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 437 Asp Trp Gln Lys Thr Ile ProAla Tyr Trp 1 5 10 438 12 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 438 Arg Trp Gly Arg Glu Gly LeuVal Ala Ala Leu Leu 1 5 10 439 12 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 439 Trp Ser Gly Thr Arg Val TrpArg Cys Val Val Thr 1 5 10 440 9 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 440 Met Ser Leu Leu Ser Tyr LeuArg Ser 1 5 441 6 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 441 Leu Asp Leu Leu Ala Ile 1 5 442 6 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide442 Arg Ile Tyr Gly Val Lys 1 5 443 11 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 443 Met Ile Trp HisMet Phe Met Ser Leu Leu Phe 1 5 10 444 11 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 444 Phe Phe Trp AlaSer Trp Met His Leu Leu Trp 1 5 10 445 16 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 445 Phe Asp Asp CysTrp Arg Glu Arg Glu Gln Phe Leu Phe Gln Ala Leu 1 5 10 15 446 13 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide446 Cys Gly Arg Ala Ser Glu Cys Phe Arg Leu Leu Glu Met 1 5 10 447 9 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide447 Arg Glu Cys Phe Gln Met Leu Glu Arg 1 5 448 14 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 448 CysSer Ile Arg Trp Asp Phe Val Pro Gly Tyr Gly Leu Cys 1 5 10 449 14 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide449 Trp Met Gln Cys Trp Asp Ser Leu Ser Leu Cys Tyr Asp Met 1 5 10 45016 PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 450 Ala Leu Leu Met Cys Glu Ser Lys Leu Ala Glu Cys Ala Arg AlaArg 1 5 10 15 451 14 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 451 Leu Ala His Cys Lys Lys Arg Lys Glu GluCys Ala Ala Gly 1 5 10 452 12 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 452 Ser Ile Asp Gly Val Tyr LeuArg Thr Ser Arg Thr 1 5 10 453 15 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 453 Ser Ile Asp Gly Val Tyr LeuArg Thr Arg Ser Arg Thr Arg Tyr 1 5 10 15 454 15 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 454 Val Arg Trp LeuArg Gly Ser Thr Leu Arg Gly Leu Arg Asp Arg 1 5 10 15 455 15 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide455 Asp Arg Gly Gly Gly Thr Val Gly Val Tyr Trp Trp Glu Ser Tyr 1 5 1015 456 11 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 456 Val Trp Gly Thr Val Gly Thr Trp Leu Glu Tyr 1 5 10457 7 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 457 Leu Met Trp Val Ser Ala Tyr 1 5 458 16 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide458 Arg Ala Ser Asp Glu Tyr Gly Ala Leu Val Arg Phe Cys Thr Asn Leu 1 510 15 459 13 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 459 Asn Tyr Trp Cys Asp Ser Asn Trp Val Cys Glu IleAla 1 5 10 460 14 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 460 Leu Ala His Cys Leu Leu Arg Leu Glu GluCys Ala Ala Gly 1 5 10 461 14 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 461 Leu Ala Leu Cys Leu Ala ArgLeu Arg Glu Cys Ala Gly Gly 1 5 10 462 11 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 462 Cys Glu Ser ArgLeu Val Glu Cys Ser Arg Met 1 5 10 463 17 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 463 Leu Leu Asp IleAla Glu Leu Lys Leu Gln Glu Cys Ala Arg Arg Cys 1 5 10 15 Asn 464 18 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide464 Lys Leu Leu Asp Ile Ala Glu Leu Lys Leu Gln Glu Cys Ala Arg Arg 1 510 15 Cys Asn 465 25 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 465 Cys Ser Thr Gly Gly Gly Leu Thr Ala GluArg Asp Ala Glu Lys Arg 1 5 10 15 Arg Trp Leu Leu Thr His Gly Gly Glu 2025 466 21 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 466 Leu Thr Ala Glu Arg Asp Ala Glu Lys Arg Arg TrpLeu Leu Thr His 1 5 10 15 Gly Gly Glu Gly Gly 20 467 22 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 467 LeuThr Ala Glu Arg Asp Ala Glu Lys Arg Arg Trp Leu Leu Thr His 1 5 10 15Gly Gly Glu Gly Gly Lys 20 468 24 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 468 Leu Thr Ala Glu Arg Asp AlaGlu Lys Arg Arg Trp Leu Leu Thr His 1 5 10 15 Gly Gly Glu Gly Gly GlyGly Gly 20 469 25 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 469 Leu Thr Ala Glu Arg Asp Ala Glu Lys ArgArg Trp Leu Leu Thr His 1 5 10 15 Gly Gly Glu Gly Gly Gly Gly Gly Lys 2025 470 6 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 470 Glu Ser Gly Trp Val Trp 1 5 471 6 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 471 AsnSer Gly Trp Val Trp 1 5 472 5 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 472 Ser Gly Trp Val Trp 1 5 473 17PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 473 Pro Leu Gly Lys Cys Glu Ala Thr Cys Arg Glu Met Ala Arg TyrPhe 1 5 10 15 Asn 474 17 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 474 Ser Leu Gln Arg Cys Glu TyrLys Leu Ala Ser Val Arg Gly Leu Cys 1 5 10 15 Asn 475 18 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 475 AspLeu Trp Tyr Leu Glu Ser Lys Leu Glu Glu Ala Ala Arg Arg Cys 1 5 10 15Asn Gly 476 15 PRT Artificial Sequence Description of ArtificialSequence Synthetic peptide 476 Pro Tyr Met Gly Thr Arg Ser Arg Ala LysLeu Leu Arg Gln Gln 1 5 10 15 477 15 PRT Artificial Sequence Descriptionof Artificial Sequence Synthetic peptide 477 Arg Asn Ala Gly Glu Arg ArgTrp Phe Lys Thr Gln Gly Trp Tyr 1 5 10 15 478 19 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 478 Met Leu Ala GluArg Asn Ala Asp Asp Arg Arg Trp Phe Asn Thr His 1 5 10 15 Gly Arg Asp479 18 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 479 Met Met Ala Asp Gly Arg Leu Arg Asn Ser Val GlyLeu Ile Leu Trp 1 5 10 15 Cys Asp 480 12 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 480 Met Leu Ala AspGly Arg Leu Arg Asn Val Val Gly 1 5 10 481 19 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 481 Leu Leu Ala AspVal Arg Arg Arg Asn Gly Val Gly Leu Leu Arg Met 1 5 10 15 Gly Arg Asp482 12 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 482 Met Leu Ala Asp Gly Arg Leu Arg Asn Phe Gly Gly 15 10 483 10 PRT Artificial Sequence Description of Artificial SequenceSynthetic peptide 483 Thr Tyr Met Thr Tyr Val Tyr Trp Leu Cys 1 5 10 4848 PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 484 Arg Phe Gly Glu Arg Trp Gly Leu 1 5 485 9 PRT ArtificialSequence Description of Artificial Sequence Synthetic peptide 485 HisTrp Leu Trp Trp Gly Trp Asn Phe 1 5 486 10 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 486 Arg Glu Cys PheGln Met Leu Glu Arg Cys 1 5 10 487 18 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 487 Ile Leu Ala HisArg Asn Ala Lys Glu Arg Arg Trp Phe Gln Lys His 1 5 10 15 Gly Arg 488 26PRT Artificial Sequence Description of Artificial Sequence Syntheticpeptide 488 Cys Ser Thr Gly Gly Gly Leu Thr Ala Glu Arg Asp Ala Glu LysArg 1 5 10 15 Arg Trp Leu Leu Thr His Gly Gly Glu Lys 20 25 489 23 PRTArtificial Sequence Description of Artificial Sequence Synthetic peptide489 Lys Gly Gly Gly Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp 1 510 15 Phe Asn Thr His Gly Arg Glu 20 490 24 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 490 Lys Ser Thr GlyGly Leu Thr Ala Glu Arg Asp Ala Glu Lys Arg Arg 1 5 10 15 Trp Leu LeuThr His Gly Gly Glu 20 491 19 PRT Artificial Sequence Description ofArtificial Sequence Synthetic peptide 491 Glu Gln Ser Asn Ser Gly TrpVal Trp Val Gly Gly Gly Gly Cys Lys 1 5 10 15 Lys Lys Cys

What is claimed is:
 1. A compound comprising a peptide chainapproximately 17 to 40 amino acids in length that binds to G-CSFR anddisplaces or prevents the binding of G-CSF at the G-CSFR, and contains asequence of amino acids having the formula LLDICELKLQECARRCN (SEQ ID NO:208).
 2. The compound of claim 1, comprising a dimer having thestructure of formula (VIII)

wherein R¹ and R² are independently selected from the sequences of aminoacids of formula (V); βA is a β-alanine residue; n1, n2, n3, n4, x and yare independently zero or one with the proviso that the sum of x and yis either one or two; and Lk is a terminal linking moiety selected fromthe group consisting of a disulfide bond, a carbonyl moiety, a C₁₋₁₂linking moiety optionally terminated with one or two —NH— linkages andoptionally substituted at one or more available carbon atoms with alower alkyl substituent, a lysine residue or a lysine amide.
 3. Thecompound of claim 1, containing a disulfide bond.
 4. The compound ofclaim 3, having the structure:


5. The compound of claim 1, wherein the N-terminus of the peptide iscoupled to a polyethylene glycol molecule.
 6. The compound of claim 1,wherein the N-terminus of the peptide is acetylated.
 7. The compound ofclaim 1, wherein the C-terminus of the peptide is amidated.